AhR MODULATORS

ABSTRACT

Provided herein are compounds, compositions and methods of using the compounds and compositions for the treatment of diseases modulated, as least in part, by AhR. The compounds are represented by formulae:wherein the letters and symbols X1, X2, Z, R1b, R1c, R1d, R1e, R2a, R2b, R2e and R2d have the meanings provided in the specification.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 17/023,980, filed Sep. 17, 2020, which is a divisional of U.S.application Ser. No. 16/268,444, filed Feb. 5, 2019, now U.S. Pat. No.10,815,250, which claims the benefit of priority under 35 U.S.C § 119(e)to U.S. Provisional Application Ser. No. 62/626,739, filed Feb. 6, 2018and U.S. Provisional Application Ser. No. 62/793,260 filed Jan. 16,2019, each of which is incorporated herein by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

Not Applicable

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

Not Applicable

BACKGROUND OF THE INVENTION

The aryl hydrocarbon receptor (AhR) is a helix-loop-helixligand-activated transcription factor that mediates biological responsesto aromatic hydrocarbons. AhR is localized in the cytoplasm, where uponbinding to a hydrocarbon based ligand agonist such as2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), it migrates to the nucleusand forms a heterodimer with aryl hydrocarbon receptor nucleartranslocator (ARNT). Formation of the AhR/ARNT complexes subsequentlyenables binding to and transcription of the xenobiotic response element(XRE) and associated genes. AhR can also activate a non-XRE dependentprotein-protein interaction pathway.

Through its XRE-dependent and independent activity, AhR modulatesnumerous critical innate and adaptive immune responses. Chief amongthose responses, AhR agonists promote development of IL-17 producingT-helper cells (Th17) and regulatory T-cells (Tregs). AhR activationfurther induces trans-differentiation of Th17 cells to Tregs andenhances the suppressive activity of Tregs. Studies have alsodemonstrated that AhR agonism results in suppression of innateinflammatory responses mediated by macrophages (e.g. Reduced LPS-inducedIL-1b, IL-6, IL-12 and TNFa expression) and dendritic cells (DCs)(inhibits activation of DCs and promotes expression of IL-10).

To mount an effective anti-tumor immune response, antigen presentingcells (APCs) are required to process, present and consequently activatehelper CD4+ T-cells (Th) and cytotoxic CD8+ T-cells (Tc) which act inconcert to effectively lyse tumor cells. Tumor cells have developedseveral mechanisms to evade the immune mediated lysis of Th and Tc. Onesuch mechanism is the release of high concentrations of kynurenine andother potential AhR ligands in the tumor microenvironment (TME). HighAhR ligand concentrations activate the AhR in the TME resulting insuppression of APCs, Th and Tc directly, as well as recruitment,generation and activation of Tregs and Th17 which further suppress theactivity of Th and Tc. Through this mechanism, tumor cells are capableof evading anti-tumor immune responses. An antagonist of the AhR pathwaywould therefore block the AhR-dependent immune evasion mechanismsemployed by malignant cells and restore effective anti-tumor immunity.

Recent insights into tumor immunobiology has revealed that malignantcells employ a composite of immune-evasion mechanisms. Blocking orenhancing these mechanisms through a combination of therapeuticapplications such as immune check point inhibition and vaccines has beendemonstrated pre-clinically and clinically to provide an optimalrestoration of the anti-tumor immune response. While it is expected thatAhR antagonism in monotherapy will restore anti-tumor immunity, acombination of an AhR modulator with a check point inhibitor and/orvaccine is predicted to work in concert with other therapeutics topotentiate the immunotherapeutic response.

Immune mechanisms regulated by AhR have also been associated withautoimmune and inflammatory diseases such as multiple sclerosis andinflammatory bowel diseases. The activation of AhR by agonists couldtherefore be beneficial for the therapeutic treatment of autoimmune andinflammatory diseases. While agonists of AhR are described in the art,there remains a need for improved compositions and methods forimmunological modulation of treating autoimmune and inflammatorydiseases via modulation of AhR.

BRIEF SUMMARY OF THE INVENTION

Provided herein are compounds, compositions and methods of using thecompounds and compositions for the treatment of diseases modulated, asleast in part, by AhR. The compounds are represented by formula (I′):

wherein the letters and symbols X¹, X², Z, R^(1b), R^(1c), R^(1d),R^(1e), R^(2a), R^(2b), R^(2c) and R^(2d) have the meanings providedbelow.

BRIEF DESCRIPTION OF THE DRAWINGS

Not Applicable

DETAILED DESCRIPTION OF THE INVENTION

Before the present invention is further described, it is to beunderstood that the invention is not limited to the particularembodiments set forth herein, and it is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the invention, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention. Unlessdefined otherwise, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs.

It must be noted that as used herein and in the appended claims, thesingular forms “a,” “an,” and “the” include plural referents unless thecontext clearly dictates otherwise. It is further noted that the claimsmay be drafted to exclude any optional element. As such, this statementis intended to serve as antecedent basis for use of such exclusiveterminology such as “solely,” “only” and the like in connection with therecitation of claim elements, or use of a “negative” limitation.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Further,the dates of publication provided may be different from the actualpublication dates, which may need to be independently confirmed.

General

The present invention is drawn to, inter alia, small molecule compoundshaving AhR modulator activity, as well as compositions thereof, andmethods of using the compounds and compositions for the treatment andprevention of the diseases, disorders and conditions described herein.

Definitions

Unless otherwise indicated, the following terms are intended to have themeaning set forth below. Other terms are defined elsewhere throughoutthe specification.

The term “alkyl”, by itself or as part of another substituent, means,unless otherwise stated, a saturated straight or branched chainhydrocarbon radical, having the number of carbon atoms designated (i.e.C₁₋₈ means one to eight carbons). Examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term“deuteroalkyl”, by itself or as part of another substituent, refers toan alkyl group wherein from one to five hydrogen atoms have beenreplaced by deuterium. An example of a “deuteroalkyl” group is −CD₃.

The term “alkylene” refers to a divalent alkyl group as defined herein.Examples of alkylene include methylene, ethylene, and the like.

The term “alkenyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical containing one or two double bonds and having the number ofcarbon atoms designated (i.e. C₂₋₆ means two to six carbons). Examplesof alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-butenyl,and the like.

The term “alkynyl”, by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain hydrocarbonradical containing a triple and having the number of carbon atomsdesignated (i.e. C₂₋₆ means two to six carbons). Examples of alkynylgroups include ethynyl, propynyl, and the like.

The term “cycloalkyl” refers to hydrocarbon rings having the indicatednumber of ring atoms (e.g., C₃₋₆ cycloalkyl) and being fully saturatedor having no more than one double bond between ring vertices.

The term “heterocycloalkyl” refers to a ring having the indicated numberof vertices (C₃₋₇ refers to a 3- to 7-membered ring) and having from oneto five heteroatoms selected from N, O, and S, which replace one to fiveof the carbon vertices, and wherein the nitrogen and sulfur atoms areoptionally oxidized, and the nitrogen atom(s) are optionallyquaternized. More specifically, the subscript refers to the total numberof ring vertices including the carbon and heteroatom ring vertices. Theheterocycloalkyl may be a monocyclic, a bicyclic or a polycylic ringsystem. Non-limiting examples of heterocycloalkyl groups includepyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam,imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine,1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide,thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline,thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine,and the like. A heterocycloalkyl group can be attached to the remainderof the molecule through a ring carbon or a heteroatom.

As used herein, a wavy line, “

”, that intersects a single, double or triple bond in any chemicalstructure depicted herein, represent the point attachment of the single,double, or triple bond to the remainder of the molecule. Additionally, abond extending to the center of a ring (e.g., a phenyl ring) is meant toindicate attachment at any of the available ring vertices. One of skillin the art will understand that multiple substituents shown as beingattached to a ring will occupy ring vertices that provide stablecompounds and are otherwise sterically compatible. For a divalentcomponent, a representation is meant to include either orientation(forward or reverse). For example, the group “—C(O)NH—” is meant toinclude a linkage in either orientation: —C(O)NH— or —NHC(O)—, andsimilarly, “—O—CH₂CH₂—” is meant to include both —O—CH₂CH₂— and—CH₂CH₂—O—.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. The terms “deuteroalkoxy is usedin its conventional sense, and refer to deuteroalkyl, as defined herein,that is attached to the remainder of the molecule via an oxygen atom.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is meant to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon group which can be a single ring ormultiple rings (up to three rings) which are fused together or linkedcovalently. Non-limiting examples of aryl groups include phenyl,naphthyl and biphenyl.

The term “heteroaryl” refers to a 5- to 10-membered aromatic ring (orfused ring system) that contains from one to five heteroatoms selectedfrom N, O, and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Aheteroaryl group can be attached to the remainder of the moleculethrough a heteroatom. Non-limiting examples of heteroaryl groups includepyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl,quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzotriazinyl,purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl,isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines,benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl,isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl,thiazolyl, furyl, thienyl and the like.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention. When a stereochemical depiction is shown, it is meantto refer the compound in which one of the isomers is present andsubstantially free of the other isomer. ‘Substantially free of’ anotherisomer indicates at least an 80/20 ratio of the two isomers, morepreferably 90/10, or 95/5 or more. In some embodiments, one of theisomers will be present in an amount of at least 99%.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. Unnatural proportions of an isotope may bedefined as ranging from the amount found in nature to an amountconsisting of 100% of the atom in question. For example, the compoundsmay incorporate radioactive isotopes, such as for example tritium (³H),iodine-125 (¹²⁵I) or carbon-14 (¹⁴C), or non-radioactive isotopes, suchas deuterium (²H) or carbon-13 (¹³C). Such isotopic variations canprovide additional utilities to those described elsewhere within thisapplication. For instance, isotopic variants of the compounds of theinvention may find additional utility, including but not limited to, asdiagnostic and/or imaging reagents, or as cytotoxic/radiotoxictherapeutic agents. Additionally, isotopic variants of the compounds ofthe invention can have altered pharmacokinetic and pharmacodynamiccharacteristics which can contribute to enhanced safety, tolerability orefficacy during treatment. All isotopic variations of the compounds ofthe present invention, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

The terms “patient” or “subject” are used interchangeably to refer to ahuman or a non-human animal (e.g., a mammal). In one embodiment, thepatient is human.

The term “spiroheterocycloalkyl” means a saturated bicyclic ring having6 to 12 ring atoms in which one of the ring atoms is nitrogen and maycontain one or two additional heteroatoms selected from N, O, andS(O)_(n), where n is an integer from 0 to 2, the remaining ring atomsbeing C and the rings are connected via a single atom is also called thespiroatom, most often a quaternary carbon (“spiro carbon”).Representative examples include, but are not limited to,2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane,2-azaspiro[3.4]octane, 2-azaspiro[3.5]-nonane,2,7-diazaspiro[4.4]nonane, and the like.

The terms “administration”, “administer” and the like, as they apply to,for example, a subject, cell, tissue, organ, or biological fluid, referto contact of, for example, an AhR modulator, a pharmaceuticalcomposition comprising same, or a diagnostic agent to the subject, cell,tissue, organ, or biological fluid. In the context of a cell,administration includes contact (e.g., in vitro or ex vivo) of a reagentto the cell, as well as contact of a reagent to a fluid, where the fluidis in contact with the cell.

The terms “treat”, “treating”, treatment” and the like refer to a courseof action (such as administering an AhR modulator or a pharmaceuticalcomposition comprising same) initiated after a disease, disorder orcondition, or a symptom thereof, has been diagnosed, observed, and thelike so as to eliminate, reduce, suppress, mitigate, or ameliorate,either temporarily or permanently, at least one of the underlying causesof a disease, disorder, or condition afflicting a subject, or at leastone of the symptoms associated with a disease, disorder, conditionafflicting a subject. Thus, treatment includes inhibiting (e.g.,arresting the development or further development of the disease,disorder or condition or clinical symptoms association therewith) anactive disease.

The term “in need of treatment” as used herein refers to a judgment madeby a physician or other caregiver that a subject requires or willbenefit from treatment. This judgment is made based on a variety offactors that are in the realm of the physician's or caregiver'sexpertise.

The terms “prevent”, “preventing”, “prevention” and the like refer to acourse of action (such as administering an AhR modulator or apharmaceutical composition comprising same) initiated in a manner (e.g.,prior to the onset of a disease, disorder, condition or symptom thereof)so as to prevent, suppress, inhibit or reduce, either temporarily orpermanently, a subject's risk of developing a disease, disorder,condition or the like (as determined by, for example, the absence ofclinical symptoms) or delaying the onset thereof, generally in thecontext of a subject predisposed to having a particular disease,disorder or condition. In certain instances, the terms also refer toslowing the progression of the disease, disorder or condition orinhibiting progression thereof to a harmful or otherwise undesiredstate.

The term “in need of prevention” as used herein refers to a judgmentmade by a physician or other caregiver that a subject requires or willbenefit from preventative care. This judgment is made based on a varietyof factors that are in the realm of a physician's or caregiver'sexpertise.

The phrase “therapeutically effective amount” refers to theadministration of an agent to a subject, either alone or as part of apharmaceutical composition and either in a single dose or as part of aseries of doses, in an amount capable of having any detectable, positiveeffect on any symptom, aspect, or characteristic of a disease, disorderor condition when administered to the subject. The therapeuticallyeffective amount can be ascertained by measuring relevant physiologicaleffects, and it can be adjusted in connection with the dosing regimenand diagnostic analysis of the subject's condition, and the like. By wayof example, measurement of the serum level of an AhR modulator (or,e.g., a metabolite thereof) at a particular time post-administration maybe indicative of whether a therapeutically effective amount has beenused.

The phrase “in a sufficient amount to effect a change” means that thereis a detectable difference between a level of an indicator measuredbefore (e.g., a baseline level) and after administration of a particulartherapy. Indicators include any objective parameter (e.g., serumconcentration) or subjective parameter (e.g., a subject's feeling ofwell-being).

The terms “inhibitors” and “antagonists”, or “activators” and “agonists”refer to inhibitory or activating molecules, respectively, for example,for the activation of, e.g., a ligand, receptor, cofactor, gene, cell,tissue, or organ. Inhibitors are molecules that decrease, block,prevent, delay activation, inactivate, desensitize, or down-regulate,e.g., a gene, protein, ligand, receptor, or cell. Activators aremolecules that increase, activate, facilitate, enhance activation,sensitize, or up-regulate, e.g., a gene, protein, ligand, receptor, orcell. An inhibitor may also be defined as a molecule that reduces,blocks, or inactivates a constitutive activity. An “agonist” is amolecule that interacts with a target to cause or promote an increase inthe activation of the target. An “antagonist” is a molecule that opposesthe action(s) of an agonist. An antagonist prevents, reduces, inhibits,or neutralizes the activity of an agonist, and an antagonist can alsoprevent, inhibit, or reduce constitutive activity of a target, e.g., atarget receptor, even where there is no identified agonist.

The terms “modulate”, “modulation” and the like refer to the ability ofa molecule (e.g., an activator or an inhibitor) to increase or decreasethe function or activity of AhR, either directly or indirectly. Amodulator may act alone, or it may use a cofactor, e.g., a protein,metal ion, or small molecule. Examples of modulators include smallmolecule compounds and other bioorganic molecules.

The “activity” of a molecule may describe or refer to the binding of themolecule to a ligand or to a receptor; to catalytic activity; to theability to stimulate gene expression or cell signaling, differentiation,or maturation; to antigenic activity; to the modulation of activities ofother molecules; and the like. The term “proliferative activity”encompasses an activity that promotes, that is necessary for, or that isspecifically associated with, for example, normal cell division, as wellas cancer, tumors, dysplasia, cell transformation, metastasis, andangiogenesis.

“Substantially pure” indicates that a component makes up greater thanabout 50% of the total content of the composition, and typically greaterthan about 60% of the total content. More typically, “substantiallypure” refers to compositions in which at least 75%, at least 85%, atleast 90% or more of the total composition is the component of interest.In some cases, the component of interest will make up greater than about90%, or greater than about 95% of the total content of the composition.

AhR and Modulation Thereof Identification of AhR Modulators PossessingDesirable Characteristics

The present invention is drawn, in part, to the identification of AhRmodulators with at least one property or characteristic that is oftherapeutic relevance. Candidate AhR modulators can be identified byusing, for example, an art-accepted assay or model, examples of whichare will be apparent to the skilled artisan. The assay used to determinethe AhR modulatory activity of the compounds described herein is setforth in the Experimental section.

After identification, candidate modulators can be further evaluated byusing techniques that provide data regarding characteristics of themodulators (e.g., pharmacokinetic parameters). Comparisons of thecandidate modulators to a reference standard (which may be the“best-of-class” of current modulators) are indicative of the potentialviability of such candidates.

AhR modulators that can serve as reference or benchmark compoundsinclude CH223191, StemRegenin-1, kynurenine, ITE, GNF351, and CB7993113.Other reference compounds subsequently identified by the skilled artisancan also be used to assess the viability of candidate AhR modulators.

Compounds

Provided herein are compound having the formula (I′):

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein:

-   -   each of ring vertices X¹ and X² is independently selected from        the group consisting of C(R^(1a)) and N;    -   Z is selected from the group consisting of:

-   -   wherein:    -   the dashed bonds are single or double bonds;        -   n is 0 or 1;        -   W is —C(O)— or —SO₂—;    -   each of ring vertices a, b, c, d, e, f, and g are independently        selected from the group consisting of O, S, N, C(R⁴) and N(R⁴),        and the bonds joining the ring vertices are independently single        or double bonds;    -   each R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) is independently        selected from the group consisting of hydrogen, deuterium,        halogen, —CN, —NO₂, —R^(c), —CO₂R^(a), —CONR^(a)R^(b),        —C(O)R^(a), —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a),        —NR^(b)C(O)₂R^(c), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)R^(b),        —OR^(a), and —S(O)₂NR^(a)R^(b); wherein each R^(a) and R^(b) is        independently selected from hydrogen, C₁₋₈ alkyl, C₃₋₆        cycloalkyl and C₁₋₈ haloalkyl, or when attached to the same        nitrogen atom can be combined with the nitrogen atom to form a        four-, five- or six-membered ring having from 0 to 2 additional        heteroatoms as ring members selected from N, O, S, SO or SO₂;        each R^(c) is independently selected from the group consisting        of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ deuteroalkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl, and wherein the aliphatic and        cyclic portions of R^(a), R^(b) and R^(c) can be further        substituted with from one to three halogen, hydroxy, C₁₋₄ alkyl,        C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, di C₁₋₄ alkylamino and        carboxylic acid groups;    -   each R^(2a), R^(2b), R^(2c) and R^(2d) is independently selected        from the group consisting of hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃        deuteroalkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ deuteroalkoxy        and C₁₋₃ haloalkoxy;    -   R³ is selected from the group consisting of hydrogen, deuterium,        C₁₋₃ alkyl, C₁₋₃ deuteroalkyl, C₁₋₃ alkylene-OR^(d), C₁₋₃        alkylene-CO₂R^(d), C₁₋₃ alkylene-NR^(d)R^(e), C₁₋₃        alkylene-CONR^(d)R^(e), C₁₋₃ alkylene-OC(O)NR^(d)R^(e), and C₁₋₃        alkylene-NR^(e)C(O)₂R^(f); or two R³ groups are combined to form        oxo (═O);    -   each R⁴ is independently selected from the group consisting of        hydrogen, halogen, —CN, —R^(e), —CO₂R^(d), —CONR^(d)R^(e),        —C(O)R^(d), —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d),        —NR^(e)C(O)₂R^(f), —NR^(d)C(O)NR^(d)R^(e), —NR^(d)R^(e),        —OR^(a), —S(O)₂NR^(d)R^(e), —X^(a)—CN, —X^(a)—CO₂R^(d),        —X^(a)—CONR^(d)R^(e), —X^(a)—C(O)R^(d), —X^(a)—OC(O)NR^(d)R^(e),        —X^(a)—NR^(e)C(O)R^(d), —X^(a)—NR^(e)C(O)₂Rt,        —X^(a)—NR^(d)C(O)NR^(d)R^(e), —X^(a)—NR^(d)R^(e), —X^(a)—OR^(d),        —X^(a)—S(O)₂NR^(d)R^(e), and —X^(a)—OP(O)(OH)₂; wherein each        X^(a) is independently C₁₋₆alkylene; and    -   each R^(d) and R^(e) is independently selected from hydrogen,        C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same        nitrogen atom can be combined with the nitrogen atom to form        either (i) a four-, five- or six-membered ring having from 0 to        3 additional heteroatoms as ring members selected from N, O,        C(O), S, SO or SO₂ or (ii) a spiroheterocycloalkyl ring;    -   each R^(f) is independently selected from the group consisting        of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ deuteroalkyl, C₃₋₆        cycloalkyl, C₃₋₆ heterocycloalkyl, phenyl and 5- or 6-membered        heteroaryl;        and wherein the aliphatic and cyclic portions of R^(d), R^(e)        and R^(f) are can be further substituted with from one to three        halogen, hydroxy, benzyloxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, amino,        C₁₋₄ alkylamino, di C₁₋₄ alkylamino, tetrazolyl, and carboxylic        acid groups.

In a first embodiment, the compounds of formula (I′), are wherein Z isselected from the group consisting of:

wherein:

-   -   the dashed bonds (i.e.,        ) are single bonds;

vertex a is selected from the group consisting of O, S, N, CH(R⁴) andN(R⁴) and each of ring vertices b, c, d, e, f, and g are independentlyselected from the group consisting of O, S, N, C(R⁴) and N(R⁴), and thebonds joining the ring vertices are independently single or double bonds(i.e., b, c, d, e, f, and g form an aromatic ring).

In one group of embodiments, the compounds of formula (I′) and compoundsof formula (I′) in a first embodiment, are wherein Z has subformula A′(formula I′A′).

In another group of embodiments, the compounds of formula (I′) andcompounds of formula (I′) in a first embodiment, are wherein Z hassubformula B′ (formula I′B′).

In yet another group of embodiments, the compounds of formula (I′) andcompounds of formula (I′) in a first embodiment, are wherein Z hassubformula C′ (formula I′C′).

In yet another group of embodiments, the compounds of formula (I′) andcompounds in any one of the embodiments above, are wherein n is 0.

In yet another group of embodiments, the compounds of formula (I′) andcompounds in any one of the embodiments above, are wherein n is 1.

Within compounds of formula (I′), compounds of formula (I′) in a firstembodiment, and embodiments referred to above as formula I′A′, inselected embodiments, Z is selected from the group consisting of:

Within above selected embodiments, in further selected embodiments, Z isA′1. Within above selected embodiments, in another further selectedembodiments, Z is A′2. Within above selected embodiments, in yet anotherfurther selected embodiments, Z is A′3. Within above selectedembodiments, in yet another further selected embodiments, Z is A′4.Within above selected embodiments, in yet another further selectedembodiments, Z is A′5. Within above selected embodiments, in yet anotherfurther selected embodiments, Z is A′6. Within above selectedembodiments, in yet another further selected embodiments, Z is A′7.Within above selected embodiments, in a further selected embodiments, Zis A′8.

Within compounds of formula (I′), compounds of formula (I′) in a firstembodiment, embodiments referred to herein as formula I′A′, and selectedand further selected embodiments thereof above, in further selectedembodiments, W is —C(O)—.

Within compounds of formula (I′), embodiments referred to herein asformula I′A′, compounds of formula (I′) in a first embodiment, andselected and further embodiments thereof above, in another furtherselected embodiments, W is —SO₂—.

Within compounds of formula (I′), compounds of formula (I′) in a firstembodiment, and embodiments referred to above as formula I′B′, inselected embodiments, Z is selected from the group consisting of:

Within above selected embodiments, in further selected embodiments, Z isB′1. Within above selected embodiments, in another further selectedembodiments Z is B′2. Within above selected embodiments, in anotherfurther selected embodiments Z is B′3. Within above selectedembodiments, in another further selected embodiments Z is B′4.

Within compounds of embodiments referred to herein as formula I′B′, andselected and further embodiments thereof above, in further selectedembodiments, W is —C(O)—.

Within compounds of embodiments referred to herein as formula I′B′ andselected and further embodiments thereof above, in another furtherselected embodiments, W is —SO₂—.

Within compounds of formula (I′), compounds of formula (I′) in firstembodiment, and embodiments referred to above as formula I′C′; inselected embodiments, Z is selected from the group consisting of:

Within above selected embodiments, in further selected embodiments, Z isC′1. Within above selected embodiments, in another further selectedembodiments, Z is C′2. Within above selected embodiments, in yet anotherfurther selected embodiments, Z is C′3. Within above selectedembodiments, in yet another further selected embodiments, Z is C′4.Within above selected embodiments, in yet another further selectedembodiments, Z is C′5. Within above selected embodiments, in yet anotherfurther selected embodiments, Z is C′6. Within above selectedembodiments, in a further selected embodiments, Z is C′7. Within aboveselected embodiments, in another further selected embodiments, Z is C′8.Within above selected embodiments, in yet another further selectedembodiments, Z is C′9. Within above selected embodiments, in yet anotherfurther selected embodiments, Z is C′10. Within above selectedembodiments, in yet another further selected embodiments, Z is C′11.Within above selected embodiments, in yet another further selectedembodiments, Z is C′12. Within above selected embodiments, in a furtherselected embodiments, Z is C′13. Within above selected embodiments, in afurther selected embodiments, Z is C′14. Within above selectedembodiments, in a further selected embodiments, Z is C′15.

Within compounds of embodiments referred to herein as formula I′C′, andselected and further embodiments thereof above, in further selectedembodiments, W is —C(O)—.

Within compounds of embodiments referred to herein as formula I′C′ andselected and further embodiments thereof above, in another furtherselected embodiments, W is —SO₂—.

In some selected embodiments, compounds of formula I′ and compounds ofany one of the embodiments above, are wherein X¹ is N.

In some selected embodiments, compounds of formula formula I′ andcompounds of any one of the above embodiments, are wherein X² is N.

In some selected embodiments, compounds of formula formula I′ andcompounds of any one of above embodiments, are wherein X¹ and X² areboth N.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein R^(1b) is selected from thegroup consisting of H, deuterium, halogen, C₁₋₄ alkyl, —OC₁₋₄ alkyl,C₁₋₄ haloalkyl, and —OC₁₋₄ haloalkyl. In further selected embodiments,R^(1b) is selected from the group consisting of H, deuterium, and CH₃.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein R^(1c) is selected from thegroup consisting of H, deuterium, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyland —OC₁₋₄ haloalkyl. In further selected embodiments, R^(1c) isselected from the group consisting of H, deuterium, fluoro, CH₂, CF₃,—OCF₂, and —OCF₃. In still further selected embodiments, R^(1c) isselected from the group consisting of H, fluoro, deuterium, and CF₃. Inanother still further selected embodiments, R^(1c) is selected from thegroup consisting of H, fluoro, deuterium, and CF₃. In another stillfurther selected embodiments, R^(1c) is selected from the groupconsisting of fluoro, deuterium, and CF₃.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein R^(1d) and R^(1e) are eachindependently selected from the group consisting of H, deuterium,halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl and OC₁₋₄ haloalkyl. In a furtherselected embodiment, R^(1d) and R^(1e) are hydrogen.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein R^(2a) is selected from thegroup consisting of H, deuterium, halogen, C₁₋₄ alkyl and C₁₋₄haloalkyl. In further selected embodiments, R^(2a) is selected from thegroup consisting of H, deuterium, fluoro, methyl, or trifluoromethyl.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein R^(2b) is selected from thegroup consisting of H, deuterium, halogen, C₁₋₄ alkyl and C₁₋₄haloalkyl. In further selected embodiments, R^(2b) is selected from thegroup consisting of H, deuterium, fluoro, methyl, or trifluoromethyl.

In some selected embodiments, compounds formula I′ and compounds of anyone of above embodiments, are wherein R^(2e) is selected from the groupconsisting of H, deuterium, halogen, C₁₋₄ alkyl and C₁₋₄ haloalkyl. Infurther selected embodiments, R^(2e) is selected from the groupconsisting of H, deuterium, fluoro, methyl, or trifluoromethyl.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein R^(2a) is selected from thegroup consisting of H, deuterium, halogen, C₁₋₄ alkyl and C₁₋₄haloalkyl. In further selected embodiments, R^(2a) is selected from thegroup consisting of H, deuterium, fluoro, methyl, or trifluoromethyl.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments are wherein each of R^(2a), R^(2b), R^(2e)and R^(2a) are independently selected from the group consisting of H,deuterium, fluoro and CH₃ and R^(1a) is hydrogen.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein each R⁴ is independentlyselected from the group consisting of H, halogen, CN, —R^(f), —CO₂R^(d),—CONR^(d)R^(e), —C(O)R^(d), —NR^(e)C(O)R^(d),—NR^(e)C(O)₂R^(f)—NR^(d)C(O)NR^(d)R^(e), —NR^(d)R^(e), —OR^(d),—X^(a)—CN, —X^(a)—CO₂R^(d), —X^(a)—CONR^(d)R^(e), —X^(a)—C(O)R^(d),—X^(a)—OC(O)NR^(d)R^(e), —X^(a)—NR^(e)C(O)R^(d), —X^(a)—NR^(e)C(O)₂R,—X^(a)—NR^(d)C(O)NR^(d)R^(e), —X^(a)—NR^(d)R^(e) and —X^(a)—OR^(d);wherein each X^(a) is independently C₁₋₄alkylene. In further selectedembodiments, each R⁴ is independently selected from the group consistingof hydrogen, halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e),—C(O)R^(d), —NR^(d)R^(e), —OR^(d), —X^(a)—CN, —X^(a)—CO₂R^(d),X^(a)—NR^(d)R^(e), and —X^(a)—OR^(d) wherein each X^(a) is independentlyC₁₋₆alkylene. In still further selected embodiments, each R⁴ isindependently H, halogen, or R^(f). In further selected embodiments,each R⁴ is independently H, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₁₋₆deuteroalkyl, or C₃₋₆cycloalkyl. In another further selectedembodiments, each R⁴ is independently H, fluoro, chloro, bromo, cyano,methyl, ethyl, propyl, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl,2-hydroxyprop-2-yl, cyanomethyl, methoxycarbonyl, ethoxycarbonyl,carboxy, morpholin-4-yl, 3-oxo-morpholin-4-yl, morpholin-4-ylmethyl,morpholin-4-ylethyl, 2-methylmorpholin-4-ylmethyl, piperidin-1-ylmethyl,piperidin-1-ylethyl, 4-hydroxypiperidin-1-ylethyl,4,4-difluoropiperidin-1-ylethyl, 4-oxopiperidin-1-ylmethyl,4-fluoropiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,1,1-dioxothiomorpholin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-ethylpiperazin-1-ylmethyl, 4-methylpiperazin-1-ylethyl,4-ethylpiperazin-1-ylethyl, 3-oxo-4-methylpiperazin-1-ylmethyl,2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl,2-oxa-7-azaspiro[3.5]nonan-7-ylethyl,6-hydroxy-2-azaspiro[3.3]heptan-2-ylmethyl,6-hydroxy-2-azaspiro[3.3]heptan-2-ylethyl,2-oxa-6-azaspiro[3.5]nonan-6-ylmethyl,2-oxa-6-azaspiro[3.5]nonan-6-ylethyl,2-oxa-6-azaspiro[3.4]octan-6-ylmethyl,2-oxa-6-azaspiro[3.4]-octan-6-ylethyl, aminocarbonyl,3-hydroxyprop-2-ylaminocarbonyl, morpholin-4-ylcarbonyl,piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, amino,dimethylaminomethyl, diethylaminoethyl, dimethylaminoethyl,diethylaminoethyl, tetrazolylmethyl, tetrazolylethyl, carboxymethyl,carboxyethyl, 3-hydroxyprop-2-ylamino, 2-hydroxyethyloxy,3-hydroxy-propyloxy, or 2,4-dioxoimidazolidin-5-yl.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein X¹ is N, X² is CH, R^(1b) is Hor CH₃, R^(1c) is CF₃, R^(2a) is H, F or CH₃, R^(2b) and R^(2d) are H,and R^(2c) is H or CH₃.

In some selected embodiments, compounds of formula I′ compounds of anyone of above embodiments, are wherein X¹ is N, X² is N, R^(1b) is H orCH₃, R^(1c) is CF₃, R^(2a) is H, F or CH₃, R^(2b) and R^(2d) are H, andR^(2c) is H or CH₃.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein X¹ is CH, X² is N, R^(1b) is Hor CH₃, R^(1c) is CF₃, R^(2a) is H, F or CH₃, R^(2b) and R^(2d) are H,and R^(2c) is H or CH₃.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein X¹ is CH, X² is CH, R^(1b) isH or CH₃, R^(1c) is CF₃, R^(2a) is H, F or CH₃, R^(2b) and R^(2d) are H,and R^(2c) is H or CH₃.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein each R³ is hydrogen orC₁₋₃alkyl.

In some selected embodiments, compounds of formula I′ and compounds ofany one of above embodiments, are wherein two R³ are combined to formoxo.

In some selected embodiments, in the compounds of formula I′ andcompounds of any one of above embodiments, when two R⁴ are present, thenone of R⁴ is H, methyl, or ethyl and the other of R⁴ is H, bromo, cyano,methyl, ethyl hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl,2-hydroxyprop-2-yl, cyanomethyl, methoxycarbonyl, ethoxycarbonyl,carboxy, morpholin-4-yl, 3-oxo-morpholin-4-yl, morpholin-4-ylmethyl,morpholin-4-ylethyl, 2-methylmorpholin-4-ylmethyl, piperidin-1-ylmethyl,piperidin-1-ylethyl, 4-hydroxypiperidin-1-ylethyl,4,4-difluoropiperidin-1-ylethyl, 4-oxopiperidin-1-ylmethyl,4-fluoropiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,1,1-dioxothiomorpholin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-ethylpiperazin-1-ylmethyl, 4-methylpiperazin-1-ylethyl,4-ethylpiperazin-1-ylethyl, 3-oxo-4-methylpiperazin-1-ylmethyl,2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl,2-oxa-7-azaspiro[3.5]nonan-7-ylethyl,6-hydroxy-2-azaspiro[3.3]heptan-2-ylmethyl,6-hydroxy-2-azaspiro[3.3]heptan-2-ylethyl,2-oxa-6-azaspiro[3.5]nonan-6-ylmethyl,2-oxa-6-azaspiro[3.5]nonan-6-ylethyl,2-oxa-6-azaspiro[3.4]octan-6-ylmethyl,2-oxa-6-azaspiro[3.4]octan-6-ylethyl, aminocarbonyl,3-hydroxyprop-2-ylaminocarbonyl, morpholin-4-ylcarbonyl,piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, amino,dimethylaminomethyl, diethylaminoethyl, dimethylaminoethyl,diethylaminoethyl, tetrazolylmethyl, tetrazolylethyl, carboxymethyl,carboxyethyl, 3-hydroxyprop-2-ylamino, 2-hydroxyethyloxy,3-hydroxypropyloxy, or 2,4-dioxoimidazolidin-5-yl.

In still other selected embodiments, the compound of formula I′ has astructure of formula (II′a), (II′b), (II′c), (II′d), (II′e) or (II′f):

In further selected embodiments, the compound has formula (II′a). Infurther selected embodiments, the compound has formula (II′b). Infurther selected embodiments, the compound has formula (II′c). Infurther selected embodiments, the compound has formula (II′d). Infurther selected embodiments, the compound has formula (II′e). Infurther selected embodiments, the compound has formula (II′f).

Within compounds of formulae (II′a) to (II′f), in further selectedembodiments, W is C(O).

Within compounds of formulae (II′a) to (II′f), in another furtherselected embodiments, W is S(O)₂.

In yet other selected embodiments, the compound of formula I′ has astructure of formula (III′a), (III′b), (III′c), or (III′d):

In further selected embodiments, the compound has formula (III′a). Infurther selected embodiments, the compound has formula (III′b). Infurther selected embodiments, the compound has formula (III′c). Infurther selected embodiments, the compound has formula (III′d).

Within compounds of formulae (III′a) to (III′d), in further selectedembodiments, W is C(O).

Within compounds of formulae (III′a) to (III′d), in another furtherselected embodiments, W is S(O)₂.

In other selected embodiments, the compound of formula I′ has astructure of formula (IV′a), (IV′b), (IV′c) or (IV′d):

In further selected embodiments, the compound has formula (IV′a). Infurther selected embodiments, the compound has formula (IV′b). Infurther selected embodiments, the compound has formula (IV′c). Infurther selected embodiments, the compound has formula (IV′d).

Within compounds of formulae (IV′a) to (IV′d), in further selectedembodiments, W is C(O).

Within compounds of formulae (IV′a) to (IV′d), in another furtherselected embodiments, W is S(O)₂.

Within compounds of formulae (IV′a) to (IV′d) and in further selectedembodiments contained therein, in a still further selected embodiments,R³ is hydrogen or C₁₋₃ alkyl, preferably R³ is hydrogen or methyl.

In other selected embodiments, the compound of formula I′ has astructure of formula (V′a), (V′b), (V′c) or (V′d):

In further selected embodiments, the compound has formula (V′a). Infurther selected embodiments, the compound has formula (V′b). In furtherselected embodiments, the compound has formula (V′c). In furtherselected embodiments, the compound has formula (V′d).

Within compounds of formulae (V′a) to (V′d) and in further selectedembodiments thereby, W is C(O).

Within compounds of formulae (V′a) to (V′d) and in another furtherselected embodiments therein, W is S(O)₂.

Within compounds of formulae (V′a) to (V′d) and in further selectedembodiments contained therein, in a still further selected embodiments,R³ is hydrogen or C₁₋₃ alkyl, preferably R³ is hydrogen or methyl.

In other selected embodiments, compounds are provided having formula(VI′a), (VI′b), (VI′c) or (VI′d):

In further selected embodiments, the compound has formula (VI′a). Infurther selected embodiments, the compound has formula (VI′b). Infurther selected embodiments, the compound has formula (VI′c). Infurther selected embodiments, the compound has formula (VI′d).

Within compounds of formulae (VI′a) to (VI′d) and in further selectedembodiments therein, W is C(O).

Within compounds of formulae (VI′a) to (VI′d) and in further selectedembodiments therein, in another further selected embodiments, W isS(O)₂.

Within compounds of formulae (VI′a) to (VI′d) and in further selectedembodiments therein, in a still further selected embodiments, R³ ishydrogen or C₁₋₃ alkyl, preferably R³ is hydrogen or methyl.

In other selected embodiments, the compound of formula I′ has astructure of formula (VII′a), (VII′b), (VII′c) or (VII′d):

In further selected embodiments, the compound has formula (VII′a). Infurther selected embodiments, the compound has formula (VII′b). Infurther selected embodiments, the compound has formula (VII′c). Infurther selected embodiments, the compound has formula (VII′d).

Within compounds of formulae (VII′a) to (VII′d) and further selectedembodiments therein, in further selected embodiments W is C(O).

Within compounds of formulae (VII′a) to (VII′d) and further selectedembodiments therein, in another further selected embodiments, W isS(O)₂.

Within compounds of formulae (VII′a) to (VII′d) and further selectedembodiments therein, in a still further selected embodiments, R³ ishydrogen or C₁₋₃ alkyl, preferably R³ is hydrogen or methyl.

In other selected embodiments, the compound of formula I′ has astructure of formula (VIII′a), (VIII′b), (VIII′c) or (VIII′d):

In further selected embodiments, the compound has formula (VIII′a). Infurther selected embodiments, the compound has formula (VIII′b). Infurther selected embodiments, the compound has formula V(III′c). Infurther selected embodiments, the compound has formula (VIII′d).

Within compounds of formulae (VIII′a) to (VIII′d) and in furtherselected embodiments therein, W is C(O).

Within compounds of formulae (VIII′a) to (VIII′d) and in furtherselected embodiments therein, W is S(O)₂.

Within compounds of formulae (VIII′a) to (VIII′d) and in furtherselected embodiments therein, in a still further selected embodiments,R³ is hydrogen or C₁₋₃ alkyl, preferably R³ is hydrogen or methyl.

Within compounds of formulae (II′a) to (II′e), (III′a) to (III′d),(IV′a) to (IV′d), (V′a) to (V′d), (VI′a) to (VI′d), (VII′a) to (VII′d),and (VIII′a) to (VIII′d) and further embodiments contained therein, infurther selected embodiments, each R⁴ is independently selected from thegroup consisting of H, halogen, CN, —R^(e), —CO₂R^(d), —CONR^(d)R^(e),—C(O)R^(d), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f), —NR^(d)C(O)NR^(d)R^(e),—NR^(d)R^(e), —OR^(d), —X^(a)—CN, —X^(a)—CO₂R^(d), —X^(a)—CONR^(d)R^(e),—X^(a)—C(O)R^(d), —X^(a)—OC(O)NR^(d)R^(e), —X^(a)—NR^(e)C(O)R^(d),—X^(a)—NR^(e)C(O)₂Rt, —X^(a)—NR^(d)C(O)NR^(d)R^(e), —X^(a)—NR^(d)R^(e)and —X^(a)—OR^(d); wherein each X^(a) is independently C₁₋₄alkylene. Infurther selected embodiments, each R⁴ is independently selected from thegroup consisting of hydrogen, halogen, —CN, —R^(f), —CO₂R^(d),—CONR^(d)R^(e), —C(O)R^(d), —NR^(d)R^(e), —OR^(d), —X^(a)—CN,—X^(a)—CO₂R^(d), X^(a)—NR^(d)R^(e), and —X^(a)—OR^(d) wherein each X^(a)is independently C₁₋₆alkylene. In further selected embodiments, each R⁴is independently H, halogen, or R^(f). In another further selectedembodiments, each R⁴ is independently H, halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆deuteroalkyl, or C₃₋₆cycloalkyl. In still anotherfurther selected embodiments, each R⁴ is independently H, fluoro,chloro, bromo, cyano, methyl, ethyl, propyl, hydroxymethyl,2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxyprop-2-yl, cyanomethyl,methoxycarbonyl, ethoxycarbonyl, carboxy, morpholin-4-yl,3-oxo-morpholin-4-yl, morpholin-4-ylmethyl, morpholin-4-ylethyl,2-methylmorpholin-4-ylmethyl, piperidin-1-ylmethyl, piperidin-1-ylethyl,4-hydroxypiperidin-1-ylethyl, 4,4-difluoropiperidin-1-ylethyl,4-oxopiperidin-1-ylmethyl, 4-fluoropiperidin-1-ylmethyl,4-hydroxypiperidin-1-ylmethyl, 1,1-dioxothiomorpholin-1-ylmethyl,4-methylpiperazin-1-ylmethyl, 4-ethylpiperazin-1-ylmethyl,4-methylpiperazin-1-ylethyl, 4-ethylpiperazin-1-ylethyl,3-oxo-4-methylpiperazin-1-ylmethyl,2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl,2-oxa-7-azaspiro[3.5]nonan-7-ylethyl,6-hydroxy-2-azaspiro[3.3]heptan-2-ylmethyl,6-hydroxy-2-azaspiro[3.3]heptan-2-ylethyl,2-oxa-6-azaspiro[3.5]nonan-6-ylmethyl,2-oxa-6-azaspiro[3.5]nonan-6-ylethyl,2-oxa-6-azaspiro[3.4]octan-6-ylmethyl,2-oxa-6-azaspiro[3.4]octan-6-ylethyl, aminocarbonyl,3-hydroxyprop-2-ylaminocarbonyl, morpholin-4-ylcarbonyl,piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, amino,dimethylaminomethyl, diethylaminoethyl, dimethylaminoethyl,diethylaminoethyl, tetrazolylmethyl, tetrazolylethyl, carboxymethyl,carboxyethyl, 3-hydroxyprop-2-ylamino, 2-hydroxyethyloxy,3-hydroxypropyloxy, or 2,4-dioxoimidazolidin-5-yl.

In still another further selected embodiments, in compounds where two R⁴are present, then one of R⁴ is H, methyl, or ethyl and the other of R⁴is H, bromo, cyano, methyl, ethyl hydroxymethyl, 2-hydroxyethyl,1-hydroxyethyl, 2-hydroxyprop-2-yl, cyanomethyl, methoxycarbonyl,ethoxycarbonyl, carboxy, morpholin-4-yl, 3-oxo-morpholin-4-yl,morpholin-4-ylmethyl, morpholin-4-ylethyl, 2-methylmorpholin-4-ylmethyl,piperidin-1-ylmethyl, piperidin-1-ylethyl, 4-hydroxypiperidin-1-ylethyl,4,4-difluoropiperidin-1-ylethyl, 4-oxopiperidin-1-ylmethyl,4-fluoropiperidin-1-ylmethyl, 4-hydroxypiperidin-1-ylmethyl,1,1-dioxothiomorpholin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,4-ethylpiperazin-1-ylmethyl, 4-methylpiperazin-1-ylethyl,4-ethylpiperazin-1-ylethyl, 3-oxo-4-methylpiperazin-1-ylmethyl,2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl,2-oxa-7-azaspiro[3.5]nonan-7-ylethyl,6-hydroxy-2-azaspiro[3.3]heptan-2-ylmethyl,6-hydroxy-2-azaspiro[3.3]heptan-2-ylethyl,2-oxa-6-azaspiro[3.5]nonan-6-ylmethyl,2-oxa-6-azaspiro[3.5]nonan-6-ylethyl,2-oxa-6-azaspiro[3.4]octan-6-ylmethyl,2-oxa-6-azaspiro[3.4]octan-6-ylethyl, aminocarbonyl,3-hydroxyprop-2-ylaminocarbonyl, morpholin-4-ylcarbonyl,piperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, amino,dimethylaminomethyl, diethylaminoethyl, dimethylaminoethyl,diethylaminoethyl, tetrazolylmethyl, tetrazolylethyl, carboxymethyl,carboxyethyl, 3-hydroxyprop-2-ylamino, 2-hydroxyethyloxy,3-hydroxypropyloxy, or 2,4-dioxoimidazolidin-5-yl;

R^(2a) is H, F or CH₃; and

R^(2e) is H or CH3.

Also, provided herein are compounds having the formula (I):

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein:

-   -   each of ring vertices X¹ and X² is independently selected from        the group consisting of C(R^(1a)) and N;    -   Z is selected from the group consisting of:

-   -   wherein the dashed bonds are single or double bonds, each of        ring vertices a, b, c, d, e and f are independently selected        from the group consisting of O, S, N, C(R⁴) and N(R⁴), and the        bonds joining the ring vertices are independently single or        double bonds;    -   each R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) is independently        selected from the group consisting of hydrogen, deuterium,        halogen, —CN, —NO₂, —R^(c), —CO₂R^(a), —CONR^(a)R^(b),        —C(O)R^(a), —OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a),        —NR^(b)C(O)₂R^(c), —NR^(a)C(O)NR^(a)R^(b), —NR^(a)R^(b),        —OR^(a), and —S(O)₂NR^(a)R^(b); wherein each R^(a) and R^(b) is        independently selected from hydrogen, C₁₋₈ alkyl, C₃₋₆        cycloalkyl and C₁₋₈ haloalkyl, or when attached to the same        nitrogen atom can be combined with the nitrogen atom to form a        four-, five- or six-membered ring having from 0 to 2 additional        heteroatoms as ring members selected from N, O, S, SO or SO₂;        each R^(c) is independently selected from the group consisting        of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ deuteroalkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, and C₃₋₆ cycloalkyl, and wherein the aliphatic and        cyclic portions of R^(a), R^(b) and R^(c) can be further        substituted with from one to three halogen, hydroxy, C₁₋₄ alkyl,        C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, di C₁₋₄ alkylamino and        carboxylic acid groups;    -   each R^(2a), R^(2b), R^(2c) and R^(2d) is independently selected        from the group consisting of hydrogen, halogen, C₁₋₃ alkyl, C₁₋₃        deuteroalkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃ deuteroalkoxy        and C₁₋₃ haloalkoxy;    -   R³ is selected from the group consisting of hydrogen, deuterium,        C₁₋₃ alkyl, C₁₋₃ deuteroalkyl, C₁₋₃ alkylene-OR^(d), C₁₋₃        alkylene-CO₂R^(d), C₁₋₃ alkylene-NR^(d)R^(e), C₁₋₃        alkylene-CONR^(d)R^(e), C₁₋₃ alkylene-OC(O)NR^(d)R^(e), and C₁₋₃        alkylene-NR^(e)C(O)₂R^(f); or two R³ groups are combined to form        oxo (═O);    -   each R⁴ is independently selected from the group consisting of        hydrogen, halogen, —CN, —R^(e), —CO₂R^(d), —CONR^(d)R^(e),        —C(O)R^(d), —OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂Rt,        —NR^(d)C(O)NR^(d)R^(e), —NR^(d)R^(e), —OR^(d),        —S(O)₂NR^(d)R^(e), —X^(a)—CN, —X^(a)—CO₂R^(d),        —X^(a)—CONR^(d)R^(e), —X^(a)—C(O)R^(d), —X^(a)—OC(O)NR^(d)R^(e),        —X^(a)—NR^(e)C(O)R^(d), —X^(a)—NR^(e)C(O)₂Rt,        —X^(a)—NR^(d)C(O)NR^(d)R^(e), —X^(a)—NR^(d)R^(e), —X^(a)—OR^(d),        and —X^(a)—S(O)₂NR^(d)R^(e); wherein each X^(a) is independently        C₁₋₆alkylene; and    -   each R^(d) and R^(e) is independently selected from hydrogen,        C₁₋₈ alkyl, and C₁₋₈ haloalkyl, or when attached to the same        nitrogen atom can be combined with the nitrogen atom to form a        four-, five- or six-membered ring having from 0 to 2 additional        heteroatoms as ring members selected from N, O, S, SO or SO₂;    -   each R^(f) is independently selected from the group consisting        of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ deuteroalkyl, C₃₋₆        cycloalkyl, C₃₋₆ heterocycloalkyl, phenyl and 5- or 6-membered        heteroaryl;        and wherein the aliphatic and cyclic portions of R^(d), R^(e)        and R^(f) are can be further substituted with from one to three        halogen, hydroxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, C₁₋₄        alkylamino, di C₁₋₄ alkylamino and carboxylic acid groups.

In one group of embodiments, the compounds of formulae (I), are thosewherein Z has subformula A (formula IA).

In another group of embodiments, the compounds of formulae (I), arethose wherein Z has subformula B (formula IB).

In yet another group of embodiments, the compounds of formulae (I), arethose wherein Z has subformula C (formula IC).

In those embodiments referred to herein as formula IA; in selectedembodiments, Z is selected from the group consisting of:

In further selected embodiments, Z is A1. In further selectedembodiments, Z is A2. In further selected embodiments, Z is A5.

In those embodiments referred to herein as formula IB; in selectedembodiments, Z is selected from the group consisting of:

In further selected embodiments, Z is B1. In further selectedembodiments, Z is B2.

In those embodiments referred to herein as formula IC; in selectedembodiments, Z is selected from the group consisting of.

In further selected embodiments, Z is C1. In further selectedembodiments, Z is C5.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein X¹ is N.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein X² is N.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein X¹ and X² areboth N.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein R^(1b) isselected from the group consisting of H, deuterium, C₁₋₄ alkyl and C₁₋₄haloalkyl. In further selected embodiments, R^(1b) is selected from thegroup consisting of H, deuterium and CH₃.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein R^(1c) isselected from the group consisting of H, deuterium, C₁₋₄ alkyl and C₁₋₄haloalkyl. In further selected embodiments, R^(1c) is selected from thegroup consisting of H, deuterium and CF₃.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein R^(1d) andR^(1e) are each independently selected from the group consisting of H,deuterium, C₁₋₄ alkyl and C₁₋₄ haloalkyl.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein R^(2a) isselected from the group consisting of H, deuterium, halogen, C₁₋₄ alkyland C₁₋₄ haloalkyl.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein R^(2b) isselected from the group consisting of H, deuterium, halogen, C₁₋₄ alkyland C₁₋₄ haloalkyl.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein R^(2c) isselected from the group consisting of H, deuterium, halogen, C₁₋₄ alkyland C₁₋₄ haloalkyl.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein R^(2a) isselected from the group consisting of H, deuterium, halogen, C₁₋₄ alkyland C₁₋₄ haloalkyl.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein each of R^(2a),R^(2b), R^(2c) and R^(2d) are independently selected from the groupconsisting of H, deuterium, fluoro and CH₃.

In some selected embodiments, compounds are provided having formula IC,wherein two R³ are combined to form oxo.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein each R⁴ isindependently selected from the group consisting of H, halogen, —R^(e),—CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂Rt,—NR^(d)C(O)NR^(d)R^(e), —NR^(d)R^(e), —OR^(d), —X^(a)—CN,—X^(a)—CO₂R^(d), —X^(a)—CONR^(d)R^(e), —X^(a)—C(O)R^(d),—X^(a)—OC(O)NR^(d)R^(e), —X^(a)—NR^(e)C(O)R^(d), —X^(a)—NR^(e)C(O)₂Rt,—X^(a)—NR^(d)C(O)NR^(d)R^(e), —X^(a)—NR^(d)R^(e) and —X^(a)—OR^(d);wherein each X^(a) is independently C₁₋₄alkylene. In further selectedembodiments, each R⁴ is independently H, halogen, or R. In furtherselected embodiments, each R⁴ is independently H, halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₁₋₆deuteroalkyl, or C₃₋₆cycloalkyl.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein X¹ is N, X² isCH, R^(1b) is H or CH₃, R^(1c) is CF₃, R^(2a) is H, F or CH₃, R^(2b) isH, and R^(2c) is H or CH₃.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein X¹ is N, X² isN, R^(1b) is H or CH₃, R^(1c) is CF₃, R^(2a) is H, F or CH₃, R^(2b) isH, and R^(2c) is H or CH₃.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein X¹ is CH, X² isN, R^(1b) is H or CH₃, R^(1c) is CF₃, R^(2a) is H, F or CH₃, R^(2b) isH, and R^(2c) is H or CH₃.

In some selected embodiments, compounds are provided having any one offormula IA, IB, IC, IA1, IA2, IA3, IA4, IA5, IA6, IA7, IA8, IB1, IB2,IB3, IB4, IC1, IC2, IC3, IC4, IC5, IC6, or IC7, wherein X¹ is CH, X² isCH, R^(1b) is H or CH₃, R^(1c) is CF₃, R^(2a) is H, F or CH₃, R^(2b) isH, and R^(2c) is H or CH₃.

In still other selected embodiments, formula (IIa), (IIb), (IIc), (IId),(IIe) or (IIf):

In further selected embodiments, each R⁴ is independently H, halogen, orR. In further selected embodiments, each R⁴ is independently H, halogen,C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆deuteroalkyl, or C₃₋₆cycloalkyl.

In yet other selected embodiments, compounds are provided having formula(IIIa), (IIIb), (IIIc) or (IIId):

In further selected embodiments, each R⁴ is independently H, halogen, orR^(f). In further selected embodiments, each R⁴ is independently H,halogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆deuteroalkyl, or C₃₋₆cycloalkyl.

In other selected embodiments, compounds are provided having formula(IVa), (IVb), (IVc) or (IVd):

In further selected embodiments, each R⁴ is independently H, halogen, orR^(f). In further selected embodiments, each R⁴ is independently H,halogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆deuteroalkyl, or C₃₋₆cycloalkyl.

In some selected embodiments, provided herein are compounds in Table 1having +++ or ++++ activity.

In some selected embodiments, the compound has the formula3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one-6,6,7,7-d4

Intermediates:

Also provided herein are intermediates of formula (X):

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein:

-   -   Q is CHO, halo, —B(OH)₂, or; and    -   Z, R^(2e), R^(2d), R^(2e), R^(2f) are as defined in compounds of        Formula (I′) and embodiments thereof described above.

In some embodiments, provided herein is an intermediate having theformula

Therapeutic and Prophylactic Uses

The present invention contemplates the use of the AhR modulatorsdescribed herein in the treatment or prevention of a broad range ofdiseases, disorders and/or conditions, and/or the symptoms thereof.While particular uses are described in detail hereafter, it is to beunderstood that the present invention is not so limited. Furthermore,although general categories of particular diseases, disorders andconditions are set forth hereafter, some of the diseases, disorders andconditions may be a member of more than one category, and others may notbe a member of any of the disclosed categories.

Oncology-related Disorders. In accordance with the present invention, anAhR modulator can be used to treat or prevent a proliferative conditionor disorder, including a cancer, for example, cancer of the uterus,cervix, breast, prostate, testes, gastrointestinal tract (e.g.,esophagus, oropharynx, stomach, small or large intestines, colon, orrectum), kidney, renal cell, bladder, bone, bone marrow, skin, head orneck, liver, gall bladder, heart, lung, pancreas, salivary gland,adrenal gland, thyroid, brain (e.g., gliomas), ganglia, central nervoussystem (CNS) and peripheral nervous system (PNS), and cancers of thehematopoietic system and the immune system (e.g., spleen or thymus). Thepresent invention also provides methods of treating or preventing othercancer-related diseases, disorders or conditions, including, forexample, immunogenic tumors, non-immunogenic tumors, dormant tumors,virus-induced cancers (e.g., epithelial cell cancers, endothelial cellcancers, squamous cell carcinomas and papillomavirus), adenocarcinomas,lymphomas, carcinomas, melanomas, leukemias, myelomas, sarcomas,teratocarcinomas, chemically-induced cancers, metastasis, andangiogenesis. The invention contemplates reducing tolerance to a tumorcell or cancer cell antigen, e.g., by modulating activity of aregulatory T-cell and/or a CD8+ T-cell (see, e.g., Ramirez-Montagut, etal. (2003) Oncogene 22:3180-87; and Sawaya, et al. (2003) New Engl. J.Med. 349:1501-09). In particular embodiments, the tumor or cancer iscolon cancer, ovarian cancer, breast cancer, melanoma, lung cancer,glioblastoma, or leukemia. In another particular embodiments, the tumoror cancer is melanoma, lung cancer, pancreatic cancer, glioblastoma, ormultiple myeloma. The use of the term(s) cancer-related diseases,disorders and conditions is meant to refer broadly to conditions thatare associated, directly or indirectly, with cancer, and includes, e.g.,angiogenesis and precancerous conditions such as dysplasia.

In certain embodiments, a cancer be metastatic or at risk of becomingmetastatic, or may occur in a diffuse tissue, including cancers of theblood or bone marrow (e.g., leukemia). In some further embodiments, thecompounds of the invention can be used to overcome T-cell tolerance.

In some embodiments, the present invention provides methods for treatinga proliferative condition, cancer, tumor, or precancerous condition withan AhR modulator and at least one additional therapeutic or diagnosticagent, examples of which are set forth elsewhere herein.

Immune-related Disorders and Disorders with an Inflammatory Component.As used herein, terms such as “immune disease”, “immune condition”,“immune disorder”, “inflammatory disease”, “inflammatory condition”,“inflammatory disorder” and the like are meant to broadly encompass anyimmune-related condition (e.g., an autoimmune disease) or a disorderwith an inflammatory component that can be treated by the AhR modulatorsdescribed herein such that some therapeutic benefit is obtained. Suchconditions frequently are inextricably intertwined with other diseases,disorders and conditions. By way of example, an “immune condition” mayrefer to proliferative conditions, such as cancer, tumors, andangiogenesis; including infections (acute and chronic), tumors, andcancers that resist eradication by the immune system.

The AhR modulators provided herein can be used to increase or enhance animmune response; to improve immunization, including increasing vaccineefficacy; and to increase inflammation. Immune deficiencies associatedwith immune deficiency diseases, immunosuppressive medical treatment,acute and/or chronic infection, and aging can be treated using thecompounds disclosed herein. The AhR modulators can also be used tostimulate the immune system of patients suffering fromiatrogenically-induced immune suppression, including those who haveundergone bone marrow transplants, chemotherapy, or radiotherapy.

In particular embodiments of the present disclosure, the AhR modulatorsare used to increase or enhance an immune response to an antigen byproviding adjuvant activity. In a particular embodiment, at least oneantigen or vaccine is administered to a subject in combination with atleast one AhR modulator as provided herein to prolong an immune responseto the antigen or vaccine. Therapeutic compositions are also providedwhich include at least one antigenic agent or vaccine component,including, but not limited to, viruses, bacteria, and fungi, or portionsthereof, proteins, peptides, tumor-specific antigens, and nucleic acidvaccines, in combination with at least one AhR modulator as providedherein.

Microbial-related Disorders. By inhibiting the immunosuppressive andanti-inflammatory activity of AhR, the present disclosure contemplatesthe use of the AhR modulators described herein in the treatment and/orprevention of any viral, bacterial, fungal, parasitic or other infectivedisease, disorder or condition for which treatment with an AhR modulatormay be beneficial. Examples of such diseases and disorders include HIVand AIDS, staphylococcal and streptococcal infections (e.g.,Staphylococcus aureus and streptococcus sanguinis, respectively),leishmania, toxoplasma, trichomonas, giardia, Candida albicans, Bacillusanthracis, and Pseudomonas aeruginosa. Compounds of the invention can beused to treat sepsis, decrease or inhibit bacterial growth, and reduceor inhibit inflammatory cytokines.

CNS-related and Neurological Disorders. Inhibition of AhR may also be animportant treatment strategy for patients with neurological,neuropsychiatric, neurodegenerative or other diseases, disorders andconditions having some association with the central nervous system,including disorders associated with impairment of cognitive function andmotor function. Examples include Parkinson's disease, extra pyramidalsyndrome (EPS), dystonia, akathisia, tardive dyskinesia, restless legsyndrome (RLS), epilepsy, periodic limb movement in sleep (PLMS),attention deficit disorders, depression, anxiety, dementia, Alzheimer'sdisease, Huntington's disease, multiple sclerosis, cerebral ischemia,hemorrhagic stroke, subarachnoid hemorrhage, and traumatic brain injury.

Other Disorders. Embodiments provided herein also contemplate theadministration of the AhR modulators described herein to a subject forthe treatment or prevention of any other disorder that may benefit fromat least some level of AhR modulation. Such diseases, disorders andconditions include, for example, cardiovascular (e.g., cardiacischemia), gastrointestinal (e.g., Crohn's disease), metabolic (e.g.,diabetes), hepatic (e.g., hepatic fibrosis, NASH, and NAFLD), pulmonary(e.g., COPD and asthma), ophthalmologic (e.g., diabetic retinopathy),and renal (e.g., renal failure) disorders.

In some embodiments, the AhR modulators provided herein may be used toinhibit statin-induced adenosine production, or reduce or decreaseincreases in blood glucose caused by a statin in a subject taking astatin (e.g., lovastatin and pravastatin)

Pharmaceutical Compositions

The AhR modulators provided herein may be in the form of compositionssuitable for administration to a subject. In general, such compositionsare “pharmaceutical compositions” comprising an AhR modulator(s) and oneor more pharmaceutically acceptable or physiologically acceptablediluents, carriers or excipients. In certain embodiments, the AhRmodulator is present in a therapeutically acceptable amount. Thepharmaceutical compositions may be used in the methods of the presentinvention; thus, for example, the pharmaceutical compositions can beadministered ex vivo or in vivo to a subject in order to practice thetherapeutic and prophylactic methods and uses described herein.

The pharmaceutical compositions of the present invention can beformulated to be compatible with the intended method or route ofadministration; exemplary routes of administration are set forth herein.Furthermore, the pharmaceutical compositions may be used in combinationwith other therapeutically active agents or compounds as describedherein in order to treat or prevent the diseases, disorders andconditions as contemplated by the present invention.

The pharmaceutical compositions containing the active ingredient (e.g.,a modulator of AhR function) may be in a form suitable for oral use, forexample, as tablets, capsules, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsions, hard or softcapsules, or syrups, solutions, microbeads or elixirs. Pharmaceuticalcompositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions, and such compositions may contain one or more agents suchas, for example, sweetening agents, flavoring agents, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets, capsules and the like contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be, for example, diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc.

The tablets, capsules and the like suitable for oral administration maybe uncoated or coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction. For example, a time-delay material such as glyceryl monostearateor glyceryl distearate may be employed. They may also be coated bytechniques known in the art to form osmotic therapeutic tablets forcontrolled release. Additional agents include biodegradable orbiocompatible particles or a polymeric substance such as polyesters,polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides,polyglycolic acid, ethylene-vinylacetate, methylcellulose,carboxymethylcellulose, protamine sulfate, or lactide/glycolidecopolymers, polylactide/glycolide copolymers, or ethylenevinylacetatecopolymers in order to control delivery of an administered composition.For example, the oral agent can be entrapped in microcapsules preparedby coacervation techniques or by interfacial polymerization, by the useof hydroxymethylcellulose or gelatin-microcapsules or poly(methylmethacrolate) microcapsules, respectively, or in a colloid drugdelivery system. Colloidal dispersion systems include macromoleculecomplexes, nano-capsules, microspheres, microbeads, and lipid-basedsystems, including oil-in-water emulsions, micelles, mixed micelles, andliposomes. Methods for the preparation of the above-mentionedformulations will be apparent to those skilled in the art.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, kaolin ormicrocrystalline cellulose, or as soft gelatin capsules wherein theactive ingredient is mixed with water or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture thereof. Such excipients can besuspending agents, for example sodium carboxymethylcellulose,methylcellulose, hydroxy-propylmethylcellulose, sodium alginate,polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents, for example a naturally-occurring phosphatide (e.g.,lecithin), or condensation products of an alkylene oxide with fattyacids (e.g., polyoxy-ethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols (e.g., forheptadecaethyleneoxycetanol), or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol (e.g.,polyoxyethylene sorbitol monooleate), or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides (e.g., polyethylene sorbitan monooleate). The aqueoussuspensions may also contain one or more preservatives.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified herein.

The pharmaceutical compositions of the present invention may also be inthe form of oil-in-water emulsions. The oily phase may be a vegetableoil, for example olive oil or arachis oil, or a mineral oil, forexample, liquid paraffin, or mixtures of these. Suitable emulsifyingagents may be naturally occurring gums, for example, gum acacia or gumtragacanth; naturally occurring phosphatides, for example, soy bean,lecithin, and esters or partial esters derived from fatty acids; hexitolanhydrides, for example, sorbitan monooleate; and condensation productsof partial esters with ethylene oxide, for example, polyoxyethylenesorbitan monooleate.

The pharmaceutical compositions typically comprise a therapeuticallyeffective amount of an AhR modulator as provided herein and one or morepharmaceutically and physiologically acceptable formulation agents.Suitable pharmaceutically acceptable or physiologically acceptablediluents, carriers or excipients include, but are not limited to,antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives(e.g., benzyl alcohol, methyl parabens, ethyl or n-propyl,p-hydroxybenzoate), emulsifying agents, suspending agents, dispersingagents, solvents, fillers, bulking agents, detergents, buffers,vehicles, diluents, and/or adjuvants. For example, a suitable vehiclemay be physiological saline solution or citrate buffered saline,possibly supplemented with other materials common in pharmaceuticalcompositions for parenteral administration. Neutral buffered saline orsaline mixed with serum albumin are further exemplary vehicles. Thoseskilled in the art will readily recognize a variety of buffers that canbe used in the pharmaceutical compositions and dosage forms contemplatedherein. Typical buffers include, but are not limited to,pharmaceutically acceptable weak acids, weak bases, or mixtures thereof.As an example, the buffer components can be water soluble materials suchas phosphoric acid, tartaric acids, lactic acid, succinic acid, citricacid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, andsalts thereof. Acceptable buffering agents include, for example, a Trisbuffer, N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES),2-(N-Morpholino)ethanesulfonic acid (MES),2-(N-Morpholino)ethanesulfonic acid sodium salt (MES),3-(N-Morpholino)propanesulfonic acid (MOPS), andN-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

After a pharmaceutical composition has been formulated, it may be storedin sterile vials as a solution, suspension, gel, emulsion, solid, ordehydrated or lyophilized powder. Such formulations may be stored eitherin a ready-to-use form, a lyophilized form requiring reconstitutionprior to use, a liquid form requiring dilution prior to use, or otheracceptable form. In some embodiments, the pharmaceutical composition isprovided in a single-use container (e.g., a single-use vial, ampoule,syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas amulti-use container (e.g., a multi-use vial) is provided in otherembodiments.

Formulations can also include carriers to protect the compositionagainst rapid degradation or elimination from the body, such as acontrolled release formulation, including liposomes, hydrogels, prodrugsand microencapsulated delivery systems. For example, a time delaymaterial such as glyceryl monostearate or glyceryl stearate alone, or incombination with a wax, may be employed. Any drug delivery apparatus maybe used to deliver an AhR modulator, including implants (e.g.,implantable pumps) and catheter systems, slow injection pumps anddevices, all of which are well known to the skilled artisan.

Depot injections, which are generally administered subcutaneously orintramuscularly, may also be utilized to release the AhR modulatorsdisclosed herein over a defined period of time. Depot injections areusually either solid- or oil-based and generally comprise at least oneof the formulation components set forth herein. One of ordinary skill inthe art is familiar with possible formulations and uses of depotinjections.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents mentioned herein. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Acceptable diluents,solvents and dispersion media that may be employed include water,Ringer's solution, isotonic sodium chloride solution, Cremophor EL™(BASF, Parsippany, N.J.) or phosphate buffered saline (PBS), ethanol,polyol (e.g., glycerol, propylene glycol, and liquid polyethyleneglycol), and suitable mixtures thereof. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed, including synthetic mono-or diglycerides. Moreover, fatty acids such as oleic acid, find use inthe preparation of injectables. Prolonged absorption of particularinjectable formulations can be achieved by including an agent thatdelays absorption (e.g., aluminum monostearate or gelatin).

The present invention contemplates the administration of the AhRmodulators in the form of suppositories for rectal administration. Thesuppositories can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials include, but are not limited to,cocoa butter and polyethylene glycols.

The AhR modulators contemplated by the present invention may be in theform of any other suitable pharmaceutical composition (e.g., sprays fornasal or inhalation use) currently known or developed in the future.

Routes of Administration

The present invention contemplates the administration of one or more AhRmodulators as provided herein, and compositions thereof, in anyappropriate manner. Suitable routes of administration include oral,parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g.,injection or implant), intraperitoneal, intracisternal, intraarticular,intraperitoneal, intracerebral (intraparenchymal) andintracerebroventricular), nasal, vaginal, sublingual, intraocular,rectal, topical (e.g., transdermal), buccal and inhalation. Depotinjections, which are generally administered subcutaneously orintramuscularly, may also be utilized to release the AhR modulatorsdisclosed herein over a defined period of time.

Particular embodiments of the present invention contemplate oraladministration.

Combination Therapy

The present invention contemplates the use of AhR modulators incombination with one or more active therapeutic agents (e.g.,chemotherapeutic agents) or other prophylactic or therapeutic modalities(e.g., radiation). In such combination therapy, the various activeagents frequently have different, complementary mechanisms of action.Such combination therapy may be especially advantageous by allowing adose reduction of one or more of the agents, thereby reducing oreliminating the adverse effects associated with one or more of theagents. Furthermore, such combination therapy may have a synergistictherapeutic or prophylactic effect on the underlying disease, disorder,or condition.

As used herein, “combination” is meant to include therapies that can beadministered separately, for example, formulated separately for separateadministration (e.g., as may be provided in a kit), and therapies thatcan be administered together in a single formulation (i.e., a“co-formulation”).

In certain embodiments, the AhR modulators are administered or appliedsequentially, e.g., where one agent is administered prior to one or moreother agents. In other embodiments, the AhR modulators are administeredsimultaneously, e.g., where two or more agents are administered at orabout the same time; the two or more agents may be present in two ormore separate formulations or combined into a single formulation (i.e.,a co-formulation). Regardless of whether the two or more agents areadministered sequentially or simultaneously, they are considered to beadministered in combination for purposes of the present invention.

The AhR modulators of the present invention may be used in combinationwith at least one other (active) agent in any manner appropriate underthe circumstances. In one embodiment, treatment with the at least oneactive agent and at least one AhR modulator of the present invention ismaintained over a period of time. In another embodiment, treatment withthe at least one active agent is reduced or discontinued (e.g., when thesubject is stable), while treatment with an AhR modulator of the presentinvention is maintained at a constant dosing regimen. In a furtherembodiment, treatment with the at least one active agent is reduced ordiscontinued (e.g., when the subject is stable), while treatment with anAhR modulator of the present invention is reduced (e.g., lower dose,less frequent dosing or shorter treatment regimen). In yet anotherembodiment, treatment with the at least one active agent is reduced ordiscontinued (e.g., when the subject is stable), and treatment with theAhR modulator of the present invention is increased (e.g., higher dose,more frequent dosing or longer treatment regimen). In yet anotherembodiment, treatment with the at least one active agent is maintainedand treatment with the AhR modulator of the present invention is reducedor discontinued (e.g., lower dose, less frequent dosing or shortertreatment regimen). In yet another embodiment, treatment with the atleast one active agent and treatment with the AhR modulator of thepresent invention are reduced or discontinued (e.g., lower dose, lessfrequent dosing or shorter treatment regimen).

Oncology-related Disorders. The present invention provides methods fortreating and/or preventing a proliferative condition, cancer, tumor, orprecancerous disease, disorder or condition with an AhR modulator and atleast one additional therapeutic or diagnostic agent.

In certain embodiments, the present invention provides methods for tumorsuppression of tumor growth comprising administration of an AhRmodulator described herein in combination with a signal transductioninhibitor (STI) to achieve additive or synergistic suppression of tumorgrowth. As used herein, the term “signal transduction inhibitor” refersto an agent that selectively inhibits one or more steps in a signalingpathway. Examples of signal transduction inhibitors (STIs) useful inmethods described herein include, but are not limited to: (i) bcr/ablkinase inhibitors (e.g., GLEEVEC); (ii) epidermal growth factor (EGF)receptor inhibitors, including kinase inhibitors and antibodies; (iii)her-2/neu receptor inhibitors (e.g., HERCEPTIN); (iv) inhibitors of Aktfamily kinases or the Akt pathway (e.g., rapamycin); (v) cell cyclekinase inhibitors (e.g., flavopiridol); and (vi) phosphatidyl inositolkinase inhibitors. Agents involved in immunomodulation can also be usedin combination with one or more AhR modulators described herein for thesuppression of tumor growth in cancer patients.

Examples of chemotherapeutic agents include, but are not limited to,alkylating agents such as thiotepa and cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines suchas benzodopa, carboquone, meturedopa, and uredopa; ethylenimines andmethylamelamines including altretamine, triethylenemelamine,trietylenephosphoramide, triethylenethiophosphaoramide andtrimethylolomelamime; nitrogen mustards such as chiorambucil,chlomaphazine, cholophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin,authramycin, azaserine, bleomycins, cactinomycin, calicheamicin,carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin,epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins,mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin,puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin,tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such asmethotrexate and 5-fluorouracil (5-FU); folic acid analogs such asdenopterin, methotrexate, pteropterin, trimetrexate; purine analogs suchas fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,5-FU; androgens such as calusterone, dromostanolone propionate,epitiostanol, mepitiostane, testolactone; anti-adrenals such asaminoglutethimide, mitotane, trilostane; folic acid replenisher such asfrolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinicacid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g.,paclitaxel and doxetaxel; abraxane; chlorambucil; gemcitabine;6-thioguanine; mercaptopurine; methotrexate; platinum and platinumcoordination complexes such as cisplatin and carboplatin; vinblastine;etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine;vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin;xeloda; ibandronate; CPT11; topoisomerase inhibitors;difluoromethylomithine (DMFO); retinoic acid; esperamicins;capecitabine; VEGF inhibitors such as bevacizumab; and pharmaceuticallyacceptable salts, acids or derivatives of any of the above.

Chemotherapeutic agents also include anti-hormonal agents that act toregulate or inhibit hormonal action on tumors such as anti-estrogens,including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone,and toremifene; and antiandrogens such as flutamide, nilutamide,bicalutamide, enzalutamide, apalutamide, abiraterone acetate,leuprolide, and goserelin; and pharmaceutically acceptable salts, acidsor derivatives of any of the above. In certain embodiments, combinationtherapy comprises administration of a hormone or related hormonal agent.

Additional treatment modalities that may be used in combination with anAhR modulator include radiotherapy, a monoclonal antibody against atumor antigen, a complex of a monoclonal antibody and toxin, a T-celladjuvant, bone marrow transplant, or antigen presenting cells (e.g.,dendritic cell therapy).

Immune Checkpoint Inhibitors. The present invention contemplates the useof the modulators of AhR function described herein in combination withimmune checkpoint inhibitors.

The tremendous number of genetic and epigenetic alterations that arecharacteristic of all cancers provides a diverse set of antigens thatthe immune system can use to distinguish tumor cells from their normalcounterparts. In the case of T cells, the ultimate amplitude (e.g.,levels of cytokine production or proliferation) and quality (e.g., thetype of immune response generated, such as the pattern of cytokineproduction) of the response, which is initiated through antigenrecognition by the T-cell receptor (TCR), is regulated by a balancebetween co-stimulatory and inhibitory signals (immune checkpoints).Under normal physiological conditions, immune checkpoints are crucialfor the prevention of autoimmunity (i.e., the maintenance ofself-tolerance) and also for the protection of tissues from damage whenthe immune system is responding to pathogenic infection. The expressionof immune checkpoint proteins can be dysregulated by tumors as animportant immune resistance mechanism.

Examples of immune checkpoints checkpoints include but are not limitedto CTLA-4, PD-1/L1, BTLA, TIM3, LAG3, OX40, 41BB, VISTA, CD96, TGFβ,CD73, CD39, A2AR, A2BR, IDO1, TDO2, Arginase, B7-H3, B7-H4. Cell-basedmodulators of anti-cancer immunity are also contemplated. Examples ofsuch modulators include but are not limited to chimeric antigen receptorT-cells, tumor infiltrating T-cells and dendritic-cells.

The present invention contemplates the use of the AhR modulatorsdescribed herein in combination with inhibitors of the aforementionedimmune-checkpoint receptors and ligands, as well as yet-to-be-describedimmune-checkpoint receptors and ligands. Certain modulators of immunecheckpoints are currently available, whereas others are in late-stagedevelopment. To illustrate, when it was approved for the treatment ofmelanoma in 2011, the fully humanized CTLA4 monoclonal antibodyipilimumab (YERVOY; Bristol-Myers Squibb) became the first immunecheckpoint inhibitor to receive regulatory approval in the US. Fusionproteins comprising CTLA4 and an antibody (CTLA4-Ig; abatcept (ORENCIA;Bristol-Myers Squibb)) have been used for the treatment of rheumatoidarthritis, and other fusion proteins have been shown to be effective inrenal transplantation patients that are sensitized to Epstein BarrVirus. PD1/PDL1 inhibitors include lambrolizumab, nivolumab,atezolizumab, avelumab, and durvalumab. PD1 inhibitors in developmentinclude pidilizumab (Cure Tech), AMP-224 and AMP-514 (GSK), PDR001(Novartis) and cemiplimab (Regeneron and Sanofi) and anti-PDL1antibodies in development include BMS-936559 (BMS) and CK-301(Checkpoint Therapeutics). Nivolumab has shown promise in patients withmelanoma, lung and kidney cancer.

The present invention encompasses pharmaceutically acceptable salts,acids or derivatives of any of the above.

Metabolic and Cardiovascular Diseases. The present invention providesmethods for treating and/or preventing certain cardiovascular- and/ormetabolic-related diseases, disorders and conditions, as well asdisorders associated therewith, with an AhR modulator and at least oneadditional therapeutic or diagnostic agent.

Examples of therapeutic agents useful in combination therapy for thetreatment of hypercholesterolemia (and atherosclerosis as well) includestatins (e.g., CRESTOR, LESCOL, LIPITOR, MEVACOR, PRAVACOL, and ZOCOR),which inhibit the enzymatic synthesis of cholesterol; bile acid resins(e.g., COLESTID, LO-CHOLEST, PREVALITE, QUESTRAN, and WELCHOL), whichsequester cholesterol and prevent its absorption; ezetimibe (ZETIA),which blocks cholesterol absorption; fibric acid (e.g., TRICOR), whichreduces triglycerides and may modestly increase HDL; niacin (e.g.,NIACOR), which modestly lowers LDL cholesterol and triglycerides; and/ora combination of the aforementioned (e.g., VYTORIN (ezetimibe withsimvastatin). Alternative cholesterol treatments that may be candidatesfor use in combination with the AhR modulators described herein includevarious supplements and herbs (e.g., garlic, policosanol, and guggul).

The present invention encompasses pharmaceutically acceptable salts,acids or derivatives of any of the above.

Immune-related Disorders and Disorders Having an Inflammatory Component.The present invention provides methods for treating and/or preventingimmune-related diseases, disorders and conditions; and diseases,disorders and conditions having an inflammatory component; with an AhRmodulator and at least one additional therapeutic or diagnostic agent.

Examples of therapeutic agents useful in combination therapy arespecific to the underlying disease, disorder or condition, and are knownto the skilled artisan.

Microbial Diseases. The present invention provides methods for treatingand/or preventing viral, bacterial, fungal and parasitic diseases,disorders and conditions, as well as disorders associated therewith,with an AhR modulator and at least one additional therapeutic ordiagnostic agent (e.g., one or more other antiviral agents and/or one ormore agents not associated with viral therapy).

Such combination therapy includes anti-viral agents targeting variousviral life-cycle stages and having different mechanisms of action,including, but not limiting to, the following: inhibitors of viraluncoating (e.g., amantadine and rimantidine); reverse transcriptaseinhibitors (e.g., acyclovir, zidovudine, and lamivudine); agents thattarget integrase; agents that block attachment of transcription factorsto viral DNA; agents (e.g., antisense molecules) that impact translation(e.g., fomivirsen); agents that modulate translation/ribozyme function;protease inhibitors; viral assembly modulators (e.g., rifampicin);antiretrovirals such as, for example, nucleoside analogue reversetranscriptase inhibitors (e.g., azidothymidine (AZT), ddl, ddC, 3TC,d4T); non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz,nevirapine); nucleotide analogue reverse transcriptase inhibitors; andagents that prevent release of viral particles (e.g., zanamivir andoseltamivir). Treatment and/or prevention of certain viral infections(e.g., HIV) frequently entail a group (“cocktail”) of antiviral agents.

Other antiviral agents contemplated for use in combination with an AhRmodulator include, but are not limited to, the following: abacavir,adefovir, amantadine, amprenavir, ampligen, arbidol, atazanavir,atripla, boceprevirertet, cidofovir, combivir, darunavir, delavirdine,didanosine, docosanol, edoxudine, emtricitabine, enfuvirtide, entecavir,famciclovir, fosamprenavir, foscarnet, fosfonet, ganciclovir,ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine,various interferons (e.g., peginterferon alfa-2a), lopinavir, loviride,maraviroc, moroxydine, methisazone, nelfinavir, nexavir, penciclovir,peramivir, pleconaril, podophyllotoxin, raltegravir, ribavirin,ritonavir, pyramidine, saquinavir, stavudine, telaprevir, tenofovir,tipranavir, trifluridine, trizivir, tromantadine, truvada, valaciclovir,valganciclovir, vicriviroc, vidarabine, viramidine, and zalcitabine.

The present invention contemplates the use of the AhR modulatorsdescribed herein in combination with antiparasitic agents. Such agentsinclude, but are not limited to, thiabendazole, pyrantel pamoate,mebendazole, praziquantel, niclosamide, bithionol, oxamniquine,metrifonate, ivermectin, albendazole, eflornithine, melarsoprol,pentamidine, benznidazole, nifurtimox, and nitroimidazole. The skilledartisan is aware of other agents that may find utility for the treatmentof parasitic disorders.

Embodiments of the present invention contemplate the use of the AhRmodulators described herein in combination with agents useful in thetreatment or prevention of bacterial disorders. Antibacterial agents canbe classified in various manners, including based on mechanism ofaction, based on chemical structure, and based on spectrum of activity.Examples of antibacterial agents include those that target the bacterialcell wall (e.g., cephalosporins and penicillins) or the cell membrane(e.g., polymyxins), or interfere with essential bacterial enzymes (e.g.,sulfonamides, rifamycins, and quinolines). Most antibacterial agentsthat target protein synthesis (e.g., tetracyclines and macrolides) arebacteriostatic, whereas agents such as the aminoglycoside arebactericidal. Another means of categorizing antibacterial agents isbased on their target specificity; “narrow-spectrum” agents targetspecific types of bacteria (e.g., Gram-positive bacteria such asStreptococcus), while “broad-spectrum” agents have activity against abroader range of bacteria. The skilled artisan is aware of types ofanti-bacterial agents that are appropriate for use in specific bacterialinfections.

Embodiments of the present invention contemplate the use of the AhRmodulators described herein in combination with agents useful in thetreatment or prevention of fungal disorders. Antifungal agents includepolyenes (e.g., amphotericin, nystatin, and pimaricin); azoles (e.g.,fluconazole, itraconazole, and ketoconazole); allylamines (e.g.,naftifine, and terbinafine) and morpholines (e.g., amorolfine); andantimetabolies (e.g., 5-fluorocytosine).

The present invention encompasses pharmaceutically acceptable salts,acids or derivatives of the agents (and members of the classes ofagents) set forth above.

Dosing

The AhR modulators provided herein may be administered to a subject inan amount that is dependent upon, for example, the goal ofadministration (e.g., the degree of resolution desired); the age,weight, sex, and health and physical condition of the subject to whichthe formulation is being administered; the route of administration; andthe nature of the disease, disorder, condition or symptom thereof. Thedosing regimen may also take into consideration the existence, nature,and extent of any adverse effects associated with the agent(s) beingadministered. Effective dosage amounts and dosage regimens can readilybe determined from, for example, safety and dose-escalation trials, invivo studies (e.g., animal models), and other methods known to theskilled artisan.

In general, dosing parameters dictate that the dosage amount be lessthan an amount that could be irreversibly toxic to the subject (themaximum tolerated dose (MTD)) and not less than an amount required toproduce a measurable effect on the subject. Such amounts are determinedby, for example, the pharmacokinetic and pharmacodynamic parametersassociated with ADME, taking into consideration the route ofadministration and other factors.

An effective dose (ED) is the dose or amount of an agent that produces atherapeutic response or desired effect in some fraction of the subjectstaking it. The “median effective dose” or ED₅₀ of an agent is the doseor amount of an agent that produces a therapeutic response or desiredeffect in 50% of the population to which it is administered. Althoughthe ED₅₀ is commonly used as a measure of reasonable expectance of anagent's effect, it is not necessarily the dose that a clinician mightdeem appropriate taking into consideration all relevant factors. Thus,in some situations the effective amount is more than the calculatedED₅₀, in other situations the effective amount is less than thecalculated ED₅₀, and in still other situations the effective amount isthe same as the calculated ED₅₀.

In addition, an effective dose of an AhR modulator, as provided herein,may be an amount that, when administered in one or more doses to asubject, produces a desired result relative to a healthy subject. Forexample, for a subject experiencing a particular disorder, an effectivedose may be one that improves a diagnostic parameter, measure, markerand the like of that disorder by at least about 5%, at least about 10%,at least about 20%, at least about 25%, at least about 30%, at leastabout 40%, at least about 50%, at least about 60%, at least about 70%,at least about 80%, at least about 90%, or more than 90%, where 100% isdefined as the diagnostic parameter, measure, marker and the likeexhibited by a normal subject.

In certain embodiments, the AhR modulators contemplated by the presentinvention may be administered (e.g., orally) at dosage levels of about0.01 mg/kg to about 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic effect.

For administration of an oral agent, the compositions can be provided inthe form of tablets, capsules and the like containing from 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 3.0, 5.0, 10.0,15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0,500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient.

In certain embodiments, the dosage of the desired AhR modulator iscontained in a “unit dosage form”. The phrase “unit dosage form” refersto physically discrete units, each unit containing a predeterminedamount of the AhR modulator, either alone or in combination with one ormore additional agents, sufficient to produce the desired effect. Itwill be appreciated that the parameters of a unit dosage form willdepend on the particular agent and the effect to be achieved.

Kits

The present invention also contemplates kits comprising an AhRmodulator, and pharmaceutical compositions thereof. The kits aregenerally in the form of a physical structure housing variouscomponents, as described below, and may be utilized, for example, inpracticing the methods described above.

A kit can include one or more of the AhR modulators disclosed herein(provided in, e.g., a sterile container), which may be in the form of apharmaceutical composition suitable for administration to a subject. TheAhR modulators can be provided in a form that is ready for use (e.g., atablet or capsule) or in a form requiring, for example, reconstitutionor dilution (e.g., a powder) prior to administration. When the AhRmodulators are in a form that needs to be reconstituted or diluted by auser, the kit may also include diluents (e.g., sterile water), buffers,pharmaceutically acceptable excipients, and the like, packaged with orseparately from the AhR modulators. When combination therapy iscontemplated, the kit may contain the several agents separately or theymay already be combined in the kit. Each component of the kit may beenclosed within an individual container, and all of the variouscontainers may be within a single package. A kit of the presentinvention may be designed for conditions necessary to properly maintainthe components housed therein (e.g., refrigeration or freezing).

A kit may contain a label or packaging insert including identifyinginformation for the components therein and instructions for their use(e.g., dosing parameters, clinical pharmacology of the activeingredient(s), including mechanism of action, pharmacokinetics andpharmacodynamics, adverse effects, contraindications, etc.). Labels orinserts can include manufacturer information such as lot numbers andexpiration dates. The label or packaging insert may be, e.g., integratedinto the physical structure housing the components, contained separatelywithin the physical structure, or affixed to a component of the kit(e.g., an ampule, tube or vial).

Labels or inserts can additionally include, or be incorporated into, acomputer readable medium, such as a disk (e.g., hard disk, card, memorydisk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape,or an electrical storage media such as RAM and ROM or hybrids of thesesuch as magnetic/optical storage media, FLASH media or memory-typecards. In some embodiments, the actual instructions are not present inthe kit, but means for obtaining the instructions from a remote source,e.g., via the internet, are provided.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention, nor are theyintended to represent that the experiments below were performed or thatthey are all of the experiments that may be performed. It is to beunderstood that exemplary descriptions written in the present tense werenot necessarily performed, but rather that the descriptions can beperformed to generate data and the like of a nature described therein.Efforts have been made to ensure accuracy with respect to numbers used(e.g., amounts, temperature, etc.), but some experimental errors anddeviations should be accounted for.

Unless indicated otherwise, parts are parts by weight, molecular weightis weight average molecular weight, temperature is in degrees Celsius (°C.), and pressure is at or near atmospheric. Standard abbreviations areused, including the following: μg=microgram; μl or μL=microliter;mM=millimolar; μM=micromolar; aa=amino acid(s); Ac₂O=acetic anhydride;AcCl=acetylchloride; ACN=acetonitrile;AIBN=2,2′-Azobis(2-methylpropionitrile); BID=twice daily;BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc₂O or(Boc)₂O=di-tert-butyl dicarbonate; bp=base pair(s); BSA=bovine serumalbumin; BW=body weight; d=doublet; dd=doublet of doublets; DEAD=diethylazodicarboxylate; DIBAL=diisobutylaluminium hydrideDIEA=N,N-diisopropylethylamine; DIPEA=N,N-diisopropylethylamine; dl ordL=deciliter; DMA=dimethylacetamide; DMAP=dimethylaminopyridine;DME=1,2-dimethoxyethane; DMEM=Dulbeco's Modification of Eagle's Medium;DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide;dppf=1,1′-Bis(diphenylphosphino)ferrocene; DTT=dithiothreitol;EDTA=ethylenediaminetetraacetic acid; ES=electrospray; EtOAc=ethylacetate; EtOH=ethanol; g=gram; h or hr=hour(s);HATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate;HEPES=4-(2-hydroxyethyl)-1-piperazineethylanesulfonic acid; HOAc=aceticacid; HPLC=high performance liquid chromatography; HPLC=high pressureliquid chromatography; i.m.=intramuscular(ly); i.p.=intraperitoneal(ly);IHC=immunohistochemistry; IPA=isopropyl alcohol; kb=kilobase(s);kDa=kilodalton; kg=kilogram; 1 or L=liter; LC=liquid chromatography;LCMS=liquid chromatography and mass spectrometry; m/z=mass to chargeratio; M=molar; m=multiplet; MeCN=acetonitrile; MeOH=methanol;MeSO₂Cl=methanesulfonylchloride; mg=milligram; min=minute(s);min=minutes; ml or mL=milliliter; mM=millimolar; MS=mass spectrometry;MsCl=methanesulfonylchloride; N=normal; NADPH=nicotinamide adeninedinucleotide phosphate; NBS=N-bromosuccinamide; ng=nanogram;nm=nanometer; nM=nanomolar; NMP=N-methylpyrrolidone; NMR=nuclearmagnetic resonance; ns=not statistically significant; nt=nucleotides(s);PBS=phosphate-buffered saline; Pd/C=palladium on carbon;Pd₂(dba)₃=Tris(debenzylideneactone) dipalladium;Pd(dppf)Cl₂=1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride;PE=petroleum ether; QD=daily; QM=monthly; QW=weekly; rac=racemic;Rt=retention time; s=singlet; s or sec=second(s); sat.=saturated; SC orSQ=subcutaneous(ly); t=triplet; TBAB=tetra-n-butylammonium bromide;TEA=triethylamine; TFA=trifluoroacetic acid; THF=tetrahydrofuran;TLC=thin layer chromatography; TMSCl=trimethylsilylchloride;TsOH=p-toluenesulfonic acid; U=unit; wt=wildtype.

Example 1 Synthesis of1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of 2-bromo-6-(trifluoromethyl)pyridin-3-amine

Into a 15-L 3-necked round-bottom flask, was placed6-(trifluoromethyl)pyridin-3-amine (200 g, 1.23 mol, 1 equiv) and ACN (8L) NBS (219.6 g, 1.23 mol, 1 equiv) was added in portions. The resultingsolution was stirred for 3 h at 0° C. The reaction mixture was thenquenched with water and the resulting solution was extracted with ethylacetate. The organic layer was concentrated and the residue was appliedonto a silica gel column and eluted with ethyl acetate/petroleum ether(1/10) to give (146 g, 48.99%) of the title compound as a yellow solid.LC-MS: (ES, m/z): [M+H]⁺ 241

Step 2: Synthesis of 3-amino-6-(trifluoromethyl)picolinonitrile

Into a 3-L 3-necked round-bottom flask under N₂ atmosphere, was placed2-bromo-6-(trifluoromethyl)pyridin-3-amine (146 g, 605.7 mmol, 1 equiv),CuCN (271 g, 3029.5 mmol, 5 equiv), and DMSO (1400 mL). The resultingsolution was stirred for 2 h at 120° C. The reaction was then quenchedwith water and the solids were filtered. The resulting solution wasextracted with ethyl acetate and the organic layer concentrated. Theresidue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1/1) to give 85 mg of the title compound as ayellow solid. LC-MS: (ES, m/z): [M+H]⁺ 187

Step 3: Synthesis of 6-(trifluoromethyl)pyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione

Into a 2-L 3-necked round-bottom flask, was placed3-amino-6-(trifluoromethyl)picolinonitrile (30 g, 160.32 mmol, 1 equiv),DMF (300 mL), and DBU (73.2 g, 480.96 mmol, 3 equiv) under CO₂atmosphere. The resulting solution was stirred for 14 h at 100° C. Thereaction mixture was quenched with water. The pH value of the solutionwas adjusted to 5 with HCl (1 mol/L) and the solids were filtered togive (15 g, 40.54%) of the title compound as a yellow solid. LC-MS: (ES,m/z): [M+H]⁺ 231.

Step 4: Synthesis of2,4-dichloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine

Into a 100 mL 3-necked round-bottom flask, was placed6-(trifluoromethyl)pyrido[3,2-d]pyrimidine-2,4 (1H,3H)-dione (15 g,64.91 mmol, 1 equiv), POCl₃ (75 mL), and PCl₅ (67.5 g, 325.05 mmol, 5equiv). The resulting solution was stirred for 6 at 105° C. Theresulting mixture was concentrated under vacuum, quenched withwater/ice, and extracted with MTBE. The combined organic layers wereconcentrated and the residue was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (1/50) to give (9.5 g, 54.59%)of the title compound as a white solid.

Step 5: Synthesis of 2-chloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine

Into a 250-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced 2,4-dichloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine (9.5 g,35.58 mmol, 1 equiv), THF (100 mL), PPh₃ (13.93 g, 53.37 mmol, 1.5equiv), SnBu₃H (10.29 g, 35.48 mmol, 1.1 equiv), and Pd(PPh₃)₄ (4.09 g,3.54 mmol, 0.1 equiv). The resulting solution was stirred for 2 h at 0°C. The resulting mixture was concentrated under vacuum and then appliedonto a silica gel column and eluted with ethyl acetate/petroleum ether(1/50) to give (4.5 g, 54.28%) of the title compound as a red solid.

Step 6: Synthesis of4-(2-(benzyloxy)ethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid

To a stirred mixture of 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid(60 g, 292.67 mmol, 1 equiv) in 2-(benzyloxy)ethan-1-ol (300 mL) wereadded Cs₂CO₃ (286.1 g, 878.00 mmol, 3.00 equiv) and CuCl₂ (3.9 g, 29.27mmol, 0.10 equiv). The resulting mixture was stirred for overnight at130° C. under nitrogen atmosphere. The reaction was quenched with waterand extracted with EtOAc. The aqueous phase was acidified to pH 2 withconc. HCl and the resulting mixture was extracted with EtOAc. Thecombined organic layers were concentrated under reduced pressure. Theresidue was purified by reverse flash chromatography under the followingconditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to35% gradient in 25 min; detector, UV 254 nm to give (19.2 g, 23.74%) ofthe title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 277.

Step 7: Synthesis of4-(2-(benzyloxy)ethoxy)-1-methyl-1H-pyrazole-5-carbonyl chloride

To a stirred solution of4-(2-(benzyloxy)ethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid (10 g,36.19 mmol, 1 equiv) and DMF (0.3 g, 3.62 mmol, 0.10 equiv) in DCM (200mL) was added (COCl)₂ (6.9 g, 54.29 mmol, 1.5 equiv) dropwise at 0° C.under nitrogen atmosphere. The resulting mixture was stirred for 3 h atroom temperature under nitrogen atmosphere and then concentrated undervacuum to give (11.5 g, crude) of the title compound as a white solid.

Step 8: Synthesis of4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamide

To a stirred solution of 4-bromo-2-methylaniline (6.2 g, 33.59 mmol, 1.1equiv) and Et₃N (4.6 g, 45.80 mmol, 1.5 equiv) in DCM (200 mL) was added4-(2-(benzyloxy)ethoxy)-1-methyl-1H-pyrazole-5-carbonyl chloride (9 g,30.54 mmol, 1 equiv) in portions at 0° C. The resulting mixture wasstirred for 1 h at room temperature and then quenched with water. Theresulting mixture was extracted with CH₂Cl₂ and the combined organiclayers were concentrated under reduced pressure. The crude product wasre-crystallized from MeOH (50 mL) to afford (13 g, 95.82%) of the titlecompound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 444, 446

Step 9: Synthesis ofN-(4-bromo-2-methylphenyl)-4-(2-hydroxyethoxy)-1-methyl-1H-pyrazole-5-carboxamide

To a stirred solution of4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamide(13 g, 29.26 mmol, 1 equiv) in DCM (130 mL) was added BCl₃ (44 mL,561.38 mmol, 19.19 equiv) dropwise at 0° C. The resulting mixture wasstirred for 5 h at room temperature. The reaction was quenched withNaHCO₃(aq.) (300 mL), extracted with CH₂Cl₂, dried over anhydrous sodiumsulfate, and filtered. The combined organic layers were concentrated togive 10.5 g (crude) of the title compound as a yellow solid. LC-MS: (ES,m/z): [M+H]⁺ 354, 356.

Step 10: Synthesis of2-((5-((4-bromo-2-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)oxy)ethylmethanesulfonate

To a stirred solution ofN-(4-bromo-2-methylphenyl)-4-(2-hydroxyethoxy)-1-methyl-1H-pyrazole-5-carboxamide(10.5 g, 29.64 mmol, 1 equiv) and Et₃N (9.0 g, 88.93 mmol, 3 equiv) inDCM (100 mL) was added MsCl (6.8 g, 59.29 mmol, 2 equiv) dropwise at 0°C. The resulting mixture was stirred for 5 h at room temperature. Thereaction mixture was quenched with water and the resulting mixture wasextracted with CH₂Cl₂. The combined organic layers were washed withwater, dried over anhydrous Na₂SO₄. After filtration, the filtrate wasconcentrated under reduced pressure to give (13.4 g, 104.57%) of thetitle compound as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 432, 434.

Step 11: Synthesis of7-(4-bromo-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]-oxazepin-8(5H)-one

To a stirred solution of2-((5-((4-bromo-2-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)-oxy)ethylmethanesulfonate (13.4 g, 31.00 mmol, 1 equiv) in DMF (200 mL, 2584.35mmol, 83.37 equiv) were added NaH (1.86 g, 77.51 mmol, 2.50 equiv) inportions at 0° C. The resulting mixture was stirred for 3 h at roomtemperature. The reaction was quenched with sat. NH₄Cl (aq.) and theresulting mixture was extracted with EtOAc. The combined organic layerswere concentrated under reduced pressure. The residue was purified bysilica gel column chromatography with PE/EtOAc (5/1) as eluent to afford(8 g, 76.77%) of the title compound as a yellow solid. LC-MS: (ES, m/z):[M+H]⁺ 336, 338.

Step 12: Synthesis of1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

To a stirred mixture of7-(4-bromo-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f]-[1,4]oxazepin-8(5H)-one (8 g, 23.80 mmol, 1 equiv) and B₂Pin₂ (7.3 g, 28.56 mmol, 1.2equiv) in dioxane (160 mL) were added KOAc (4.7 g, 47.59 mmol, 2 equiv)and Pd(dppf)Cl₂ (1.7 g, 2.38 mmol, 0.1 equiv). The resulting mixture wasstirred for overnight at 80° C. under nitrogen atmosphere and themixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with PE/EtOAc (3/1) aseluent to afford (7.1 g, 77.85%) of the title compound as a white solid.LC-MS: (ES, m/z): [M+H]⁺ 384.

Step 13: Synthesis of1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

To a stirred solution of1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (140 mg, 0.37 mmol, 1 equiv) and2-chloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine (140 mg, 0.60 mmol,1.64 equiv) in t-BuOH (3 mL) were added H₂O (0.33 mL), K₂CO₃ (151.5 mg,1.10 mmol, 3 equiv) and AMPhosPdCl₂ (77.4 mg, 0.11 mmol, 0.3 equiv). Theresulting mixture was stirred for overnight at 80° C. under nitrogenatmosphere and then diluted with water. The resulting mixture wasextracted with EtOAc and the combined organic layers were concentratedunder reduced pressure. The residue was purified by Prep-TLC(CH₂Cl₂/MeOH=50/1) to afford (33.5 mg, 20.18%) of the title compound asa yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 455; ¹¹H-NMR: (300 MHz, CD₃Cl,ppm): δ 2.44 (s, 3H), 4.00-4.02 (m, 2H), 4.18 (s, 3H), 4.53-4.55 (m,2H), 7.26-7.36 (m, 2H), 8.14-8.17 (d, 1H), 8.61 (d, 1H), 8.66 (s, 1H),9.83 (s, 1H).

Example 2 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of 6-(trifluoromethyl)quinazoline-2,4 (1H,3H)-dione

To a stirred solution of 2-amino-5-(trifluoromethyl)benzonitrile (30 g,161.17 mmol, 1 equiv) in DMF (900 mL) was added DBU (73.6 g, 483.46mmol, 3.00 equiv). The resulting mixture was stirred overnight at 100°C. under carbon dioxide atmosphere and then diluted with water. Thereaction mixture was acidified to pH 5 with HCl (aq.), filtered, and thefilter cake was washed with water. The resulting solid was dried in anoven under reduced pressure to give (32 g, 86.27%) of the title compoundas a light yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 230

Step 2: Synthesis of 2,4-dichloro-6-(trifluoromethyl)quinazoline

Into a 1 L 3-necked round-bottom flask were added6-(trifluoromethyl)quinazoline-2,4 (1H,3H)-dione (1:1) (57.8 g, 256.36mmol, 1 equiv), PCl₅ (266.9 g, 1281.80 mmol, 5.00 equiv) and POCl₃ (295mL). The resulting mixture was stirred for overnight at 120° C. and thenconcentrated under reduced pressure. The residue was quenched withwater/ice at 0° C. and the resulting mixture was extracted with MTBE.The combined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography with PE aseluent to afford (50.0 g, 74.79%) of the title compound as a lightyellow solid. GC-MS: (ES, m/z): [M]266

Step 3: Synthesis of 2-chloro-6-(trifluoromethyl)quinazoline

To a stirred solution of 2,4-dichloro-6-(trifluoromethyl)quinazoline (58g, 218.05 mmol, 1 equiv) and tributylstannane (74.7 g, 256.64 mmol, 1.10equiv) in THF (623 mL) were added Pd(pph₃)₄ (27.0 g, 23.33 mmol, 0.1equiv) under nitrogen atmosphere. The resulting mixture was stirredovernight at room temperature under nitrogen atmosphere. The resultingmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography with PE/EtOAc (10/1) aseluent to afford the title compound (28 g, 55.36%) as a yellow solid.LC-MS: (ES, m/z): [M+H]⁺ 233.

Step 4: Synthesis of ethyl1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylate

Into a 50-mL 3-necked round-bottom flask purged under nitrogenatmosphere, was placed ethyl 4-methyl-1H-pyrazole-5-carboxylate (2 g,12.97 mmol, 1 equiv), 2-(benzyloxy)ethan-1-ol (2.0 g, 13.14 mmol, 1.01equiv), DIAD (3.9 g, 19.46 mmol, 1.5 equiv), and PPh₃ (5.1 g, 19.46mmol, 1.5 equiv) in THF (20 mL). The resulting solution was stirred forovernight at room temperature. After concentrating the reaction mixtureunder vacuum, the residue was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (1/50) to give (3 g, 80.20%)of the title compound as colorless oil. LC-MS: (ES, m/z): [M+H]⁺ 288

Step 5: Synthesis of1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylic acid

Into a 50-mL 3-necked round-bottom flask, was placed ethyl1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylate (2.9 g, 10.06mmol, 1 equiv), NaOH (4M, 2 equiv), and EtOH (15 mL). The resultingsolution was stirred for 2 h at 50° C. and then diluted with H₂O. Theresulting mixture was concentrated to remove EtOH. The pH value of thesolution was adjusted to 4 with HCl (1 mol/L). The resulting solutionwas extracted with ethyl acetate, dried over anhydrous sodium sulfate,and concentrated to give (2.1 g, 80.22%) of the title compound as awhite solid. LC-MS: (ES, m/z): [M+H]⁺ 260

Step 6: Synthesis of1-(2-(benzyloxy)ethyl)-N-(4-bromo-2-methylphenyl)-4-methyl-1H-pyrazole-5-carboxamide

Into a 50-mL 3-necked round-bottom flask, was placed1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylic acid (1.2 g,4.61 mmol, 1 equiv), 4-bromo-2-methylaniline (1.3 g, 6.99 mmol, 1.52equiv), HATU (2.6 g, 6.92 mmol, 1.5 equiv), DIEA (1.2 g, 9.22 mmol, 2equiv), and DMF (15 mL). The resulting solution was stirred forovernight at room temperature. The resulting solution was diluted withEtOAc and washed with H₂O. The resulting mixture was concentrated undervacuum and the residue was applied onto a silica gel column and elutedwith ethyl acetate/petroleum ether (1/10) to give (1.6 g, 81.03%) of thetitle compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 428, 430

Step 7: Synthesis ofN-(4-bromo-2-methylphenyl)-1-(2-hydroxyethyl)-4-methyl-1H-pyrazole-5-carboxamide

Into a 50-mL 3-necked round-bottom flask under nitrogen atmosphere, wasplaced1-(2-(benzyloxy)ethyl)-N-(4-bromo-2-methylphenyl)-4-methyl-1H-pyrazole-5-carboxamide(1 g, 1 equiv), and BCl₃ (1 mol/mL, 5 mL) was added dropwise at 0° C.The resulting solution was stirred for 1 h at 0° C. and then quenchedwith NaHCO₃. The resulting solution was extracted with ethyl acetate andthe organic layers were combined. The organic layer was washed with H₂O,dried over anhydrous sodium sulfate and concentrated to give (512 mg,67.65%) of the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺338, 340.

Step 8: Synthesis of2-(5-((4-bromo-2-methylphenyl)carbamoyl)-4-methyl-1H-pyrazol-1-yl)ethylmethanesulfonate

Into a 25-mL 3-necked round-bottom flask, was placedN-(4-bromo-2-methylphenyl)-1-(2-hydroxyethyl)-4-methyl-1H-pyrazole-5-carboxamide(312 mg, 0.92 mmol, 1 equiv), DCM (5 mL), and MsCl (158.5 mg, 1.38 mmol,1.5 equiv) was added dropwise at 0° C. The resulting solution wasstirred for 1 h at RT and then quenched with water. The resultingsolution was extracted with dichloromethane and the organic layerscombined. The resulting mixture was washed with H₂O, dried, filtered andconcentrated to give (416 mg) of the title compound as a crude product.LC-MS: (ES, m/z): [M+H]⁺ 416, 418.

Step 9: Synthesis of5-(4-bromo-2-methylphenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, was placed2-(5-((4-bromo-2-methylphenyl)carbamoyl)-4-methyl-1H-pyrazol-1-yl)ethylmethanesulfonate (416 mg, 1.00 mmol, 1 equiv), DMF (5 mL, 64.61 mmol,64.65 equiv), and NaH (36.0 mg, 1.50 mmol, 1.5 equiv) was added inportions at 0° C. The resulting solution was stirred for 1 h at 0° C.The reaction mixture was then quenched by added to 20 mL of NH₄Cl andextracted with ethyl acetate. The organic layer was washed with H₂O andthen concentrated. The residue was applied onto a prep-TLC with ethylacetate/petroleum ether (1/5) to give (300 mg, 93.76%) of the titlecompound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 320, 322

Step 10: Synthesis of3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 8-mL sealed tube purged under nitrogen atmosphere, was placed5-(4-bromo-2-methylphenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (280 mg, 0.87 mmol, 1 equiv),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(333.1 mg, 1.31 mmol, 1.5 equiv), Pd(dppf)Cl₂ (96.0 mg, 0.13 mmol, 0.15equiv), and KOAc (171.6 mg, 1.75 mmol, 2 equiv), in dioxane (3 mL). Theresulting solution was stirred for overnight at 80° C. The resultingmixture was concentrated under vacuum and the residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1/5) togive (204 mg, 63.52%) of the title compound as a white solid. LC-MS:(ES, m/z): [M+H]⁺ 367.

Step 11: Synthesis of2-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 50-mL 3-necked round-bottom flask under nitrogen atmosphere, wasplaced3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one (180 mg, 0.49 mmol, 1 equiv),2-chloro-6-(trifluoromethyl)-quinazoline (114.0 mg, 0.49 mmol, 1.00equiv), Pd(PPh₃)₄ (85.0 mg, 0.07 mmol, 0.15 equiv), and K₂CO₃ (203.2 mg,1.47 mmol, 3.00 equiv) in toluene (5.4 mL) and EtOH (2.7 mL). Theresulting solution was stirred for overnight at 80° C. The resultingsolution was diluted with H₂O, extracted with ethyl acetate, and theorganic layers were combined. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1/2) to give (31.8mg, 14.83%) of the title compound as a light yellow solid. LC-MS: (ES,m/z): [M+H]⁺ 438;

¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 9.89 (s, 1H), 8.71 (s, 1H), 8.54 (d,1H), 8.47 (d, 1H), 8.27 (t, 2H), 7.54 (d, 1H), 7.46 (s, 1H), 4.51 (t,2H), 4.29 (m, 1H), 3.91 (m, 1H), 2.33 (s, 3H), 2.24 (s, 3H).

Example 3 Synthesis of5-(2,5-dimethyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carbonyl chloride

Into a 250-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced 1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylic acid(6.4 g, 24.59 mmol, 1 equiv), prepared as described in Example 2 above,DCM (60 mL, 943.80 mmol, 38.39 equiv), DMF (0.2 g, 2.74 mmol, 0.11equiv.), and (COCl)₂ (3.4 g, 27.05 mmol, 1.1 equiv) was added dropwiseto the above solution at 0° C. The resulting solution was stirred for 1h at RT and then concentrated under vacuum to give 6.9 g of the titlecompound as a crude product.

Step 2: Synthesis of1-(2-(benzyloxy)ethyl)-N-(4-bromo-2,5-dimethylphenyl)-4-methyl-1H-pyrazole-5-carboxamide

Into a 100 mL 3-necked round-bottom flask was added4-bromo-2,5-dimethylaniline (3.3 g, 16.50 mmol, 1 equiv), DCM (50 mL),and Et₃N (3.3 g, 32.61 mmol, 1.98 equiv). To the above mixture1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carbonyl chloride (4.6 g,16.50 mmol, 1 equiv) in 20 mL of DCM was added dropwise at 0° C. Theresulting mixture was stirred for additional 1 h at room temperature.The reaction mixture was quenched with water and the aqueous layer wasextracted with CH₂Cl₂. The combined organic layer was dried overanhydrous sodium sulfate and concentrated under vacuum. The crudeproduct was re-crystallized from MeOH (50 mL) to afford (5.4 g, 73.97%)of the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 442.

Step 3: Synthesis ofN-(4-bromo-2,5-dimethylphenyl)-1-(2-hydroxyethyl)-4-methyl-1H-pyrazole-5-carboxamide

Into a 250-mL 3-necked round-bottom flask under nitrogen atmosphere wasplaced1-(2-(benzyloxy)ethyl)-N-(4-bromo-2,5-dimethylphenyl)-4-methyl-1H-pyrazole-5-carboxamide(5.4 g, 1 equiv), DCM (50 mL), and BCl₃ (18.3 mL, 1M in DCM, 1.5 equiv)was added dropwise at 0° C. The resulting solution was stirred for 1 hat RT. After quenching with NaHCO₃(aq.), the reaction mixture wasextracted with dichloromethane. The combined organic layer was washedwith H₂O, dried over anhydrous sodium sulfate and concentrated undervacuum to give (4.1 g, 95.35%) of the title compound as a white solid.LC-MS: (ES, m/z): [M+H]⁺ 352.

Step 4: Synthesis of2-(5-((4-bromo-2,5-dimethylphenyl)carbamoyl)-4-methyl-1H-pyrazol-1-yl)ethylmethanesulfonate

Into a 100-mL 3-necked round-bottom flask under nitrogen atmosphere, wasplacedN-(4-bromo-2,5-dimethylphenyl)-1-(2-hydroxyethyl)-4-methyl-1H-pyrazole-5-carboxamide(4.1 g, 11.64 mmol, 1 equiv), DCM (40 mL), Et₃N (2.4 g, 23.72 mmol, 2.04equiv), and MsCl (2.0 g, 17.46 mmol, 1.50 equiv) was added dropwise tothe above mixture at 0° C. The resulting solution was stirred for 1 h atRT. The reaction mixture was then quenched with water. The resultingsolution was extracted with dichloromethane and the organic layerscombined. The organic layer was washed with H₂O, dried over anhydroussodium sulfate and concentrated under vacuum to give 4.75 g of the titlecompound as a crude product. LC-MS: (ES, m/z): [M+H]⁺ 430.

Step 5: Synthesis of5-(4-bromo-2,5-dimethylphenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 100-mL 3-necked round-bottom flask under nitrogen atmosphere, wasadded2-(5-((4-bromo-2,5-dimethylphenyl)carbamoyl)-4-methyl-1H-pyrazol-1-yl)ethylmethanesulfonate (4.75 g, 11.04 mmol, 1 equiv), and DMF (50 mL), and NaH(0.4 g, 16.67 mmol, 1.51 equiv) was added at 0° C. The resultingsolution was stirred for 1 h at RT and then quenched with NH₄Cl (aq.).The resulting solution was extracted with ethyl acetate and the combinedorganic layer was washed with H₂O and concentrated. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/petroleumether (1:5) to give (3.1 g, 84.03%) of the title compound as a whitesolid. LC-MS: (ES, m/z): [M+H]⁺ 334.

Step 6: Synthesis of5-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 100-mL 3-necked round-bottom flask under nitrogen atmosphere, wasplaced5-(4-bromo-2,5-dimethylphenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (3.1 g, 9.28 mmol, 1 equiv), B₂Pin₂ (3.54 g, 13.92 mmol, 1.5equiv), dioxane (30 mL), KOAc (1.8 g, 18.34 mmol, 1.98 equiv), andPd(dppf)Cl₂ (2.0 g, 2.78 mmol, 0.3 equiv). The resulting solution wasstirred overnight at 80° C. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column and eluted withethyl acetate/petroleum ether (1:5) to give (3 g, 84.83%) of the titlecompound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 382

Step 7: Synthesis of5-(2,5-dimethyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 50-mL 3-necked round-bottom flask under nitrogen atmosphere, wasplaced5-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (1 g, 2.62 mmol, 1 equiv),2-chloro-6-(trifluoromethyl)quinazoline (0.7 g, 2.89 mmol, 1.1 equiv),K₂CO₃ (1.1 g, 7.87 mmol, 3 equiv), toluene (14 mL), EtOH (7 mL), andPd(PPh₃)₄ (0.5 g, 0.39 mmol, 0.15 equiv). The resulting solution wasstirred for 12 at 80° C. The resulting mixture was diluted with andextracted with ethyl acetate. The combined organic layer wasconcentrated under reduced pressure. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1:2) togive (307.1 mg, 25.94%) of the title compound as a white solid. LC-MS:(ES, m/z): [M+H]⁺ 452; ¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 9.91 (s, 1H),8.75 (s, 1H), 8.31 (d, 1H), 8.26 (d, 1H), 7.95 (s, 1H), 7.47 (s, 1H),7.36 (s, 1H), 4.51-4.54 (t, 2H), 4.26-4.32 (m, 1H), 3.90-3.95 (m, 1H),2.59 (s, 3H), 2.27 (s, 6H).

Example 4 Synthesis of1-methyl-6-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Step 1: Synthesis of methyl 4-allyl-1-methyl-1H-pyrazole-5-carboxylate

To a stirred solution of methyl4-bromo-1-methyl-1H-pyrazole-5-carboxylate (100 g, 456.54 mmol, 1 equiv)and tributyl(prop-2-en-1-yl)stannane (166.3 g, 502.20 mmol, 1.1 equiv)in DMF (1000 mL) was added Pd(PPh₃)₄ (26.4 g, 22.83 mmol, 0.05 equiv).The resulting mixture was stirred overnight at 100° C. under nitrogenatmosphere and then was quenched with water. The resulting mixture wasextracted with EtOAc. The combined organic layers were concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography with PE/EtOAc (50/1) as eluent to afford (80 g, 97.24%)of the title compound as a yellow oil. LC-MS: (ES, m/z): [M+H]⁺ 181.

Step 2. Synthesis of 4-allyl-1-methyl-1H-pyrazole-5-carboxylic acid

Into a 2-L 3-necked round-bottom flask, was placed methyl4-allyl-1-methyl-1H-pyrazole-5-carboxylate (84 g, 466.13 mmol, 1 equiv),MeOH (840 mL, 20747.08 mmol, 44.51 equiv), NaOH (37.3 g, 932.57 mmol,2.00 equiv). The resulting solution was stirred for 2 h at 50° C. andthen diluted with H₂O. The resulting mixture was concentrated undervacuum to remove CH₃OH. The pH of the solution was adjusted to 5 withHCl (1 mol/L). The resulting solution was extracted with ethyl acetateand the organic layers combined and concentrated to give (61 g, 78.75%)of the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 167.

Step 3: Synthesis of 4-allyl-1-methyl-1H-pyrazole-5-carbonyl chloride

Into a 500-mL round-bottom flask was placed4-allyl-1-methyl-1H-pyrazole-5-carboxylic acid (20 g, 120.35 mmol, 1equiv) in DCM (200 mL, 3146.01 mmol, 26.14 equiv), and DMF (0.9 g, 12.04mmol, 0.1 equiv). Oxalyl chloride (22.9 g, 180.42 mmol, 1.50 equiv) wasadded dropwise over 10 min at 0° C. The resulting reaction mixture wasconcentrated to give (21 g, 94.51%) of the title compound as a crudeproduct.

Step 4: Synthesis of4-allyl-N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 500-mL 3-necked round-bottom flask, was placed4-bromo-2-methylaniline (25.4 g, 136.52 mmol, 1.20 equiv), Et₃N (17.3 g,170.62 mmol, 1.5 equiv), and DCM.4-Allyl-1-methyl-1H-pyrazole-5-carbonyl chloride (21 g, 113.75 mmol, 1equiv) was added dropwise with stirring at 0° C. The resulting solutionwas stirred for 30 min at rt and then quenched with water. The resultingsolution was extracted with DCM and the organic layers combined andconcentrated. The crude product was purified by re-crystallization fromCH₃OH to give (33 g, 86.81%) of the title compound as a white solid.LC-MS: (ES, m/z): [M+H]⁺ 334.

Step 5: Synthesis ofN-(4-bromo-2-methylphenyl)-4-(2,3-dihydroxypropyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 500-mL 3-necked round-bottom flask was placed4-allyl-N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamide(21 g, 62.83 mmol, 1 equiv), NMO (22.1 g, 188.50 mmol, 3 equiv), THF(210 mL, 2.91 mmol, 0.05 equiv), H₂O (21 mL, 1165.68 mmol, 18.55 equiv),and OsO₄ (0.8 g, 3.15 mmol, 0.05 equiv). The resulting solution wasstirred for 30 min at room temperature. The reaction mixture wasquenched with 300 mL of NaS₂O₄. The resulting solution was extractedwith ethyl acetate, water and then concentrated to give (37 g, 159.92%)of the title compound as a crude product. LC-MS: (ES, m/z): [M+H]⁺ 368.

Step 6: Synthesis ofN-(4-bromo-2-methylphenyl)-1-methyl-4-(2-oxoethyl)-1H-pyrazole-5-carboxamide

Into a 500-mL 3-necked round-bottom flask, was placedN-(4-bromo-2-methylphenyl)-4-(2,3-dihydroxypropyl)-1-methyl-1H-pyrazole-5-carboxamide(37 g, 100.48 mmol, 1 equiv), MeOH (370 mL), H₂O (37 mL), and NaIO₄(43.0 g, 201.04 mmol, 2.00 equiv). The resulting solution was stirredfor 30 min at room temperature, diluted with 370 mL of H₂O, and theresulting mixture was concentrated. The solids were filtrated, washedwith H₂O and dried to give 35 g (crude) of the title compound as a whitesolid. LC-MS: (ES, m/z): [M+H]⁺ 336.

Step 7: Synthesis ofN-(4-bromo-2-methylphenyl)-4-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 1 L 3-necked round-bottom flask was placedN-(4-bromo-2-methylphenyl)-1-methyl-4-(2-oxoethyl)-1H-pyrazole-5-carboxamide(35 g, 104.11 mmol, 1 equiv) in MeOH (350 mL). NaBH₄ (4.7 g, 124.23mmol, 1.19 equiv) was added in portions at 0° C. The resulting solutionwas stirred for 30 min at rt and then quenched with NH₄Cl solution (350mL). The resulting mixture was concentrated and the solids werecollected by filtration, washed with H₂O, dried to give (30 g, 85.20%)of the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 338.

Step 8: Synthesis of2-(5-((4-bromo-2-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)ethylmethanesulfonate

Into a 1-L round-bottom flask, was placedN-(4-bromo-2-methylphenyl)-4-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide(30 g, 88.70 mmol, 1 equiv), DCM (300 mL), and Et₃N (13.5 g, 133.41mmol, 1.50 equiv). Methanesulfonyl chloride (15.2 g, 132.69 mmol, 1.50equiv) was added dropwise with stirring at 0° C. The resulting solutionwas stirred for 30 min at rt and then quenched with water. The resultingsolution was extracted with dichloromethane and concentrated to give (42g, 113.74%) of the title compound as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 416.

Step 9: Synthesis of6-(4-bromo-2-methylphenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Into a 1 L 3-necked round-bottom flask was placed2-(5-((4-bromo-2-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)ethylmethanesulfonate (42 g, 100.89 mmol, 1 equiv), and DMF (420 mL, 5427.14mmol, 53.79 equiv). NaH (3.6 g, 150.01 mmol, 1.49 equiv) was added inportions at 0° C. The resulting solution was stirred for 30 min at roomtemperature and then quenched with NH₄Cl. The solids were collected byfiltration. The crude product was purified by re-crystallization from PEto give (23 g, 71.20%) of the title compound as a white solid. LC-MS:(ES, m/z): [M+H]⁺.

Step 10: Synthesis of1-methyl-6-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Into a 500-mL 4-necked round-bottom flask under N₂ atmosphere, wasplaced B₂Pin₂ (23.8 g, 93.72 mmol, 1.50 equiv),6-(4-bromo-2-methylphenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(20 g, 62.46 mmol, 1 equiv), Pd(dppf)Cl₂ (2.3 g, 3.12 mmol, 0.05 equiv),and KOAc (12.3 g, 124.93 mmol, 2 equiv) in dioxine (400 mL). Theresulting solution was stirred overnight at 80° C. The resulting mixturewas concentrated and the residue was applied onto a silica gel columnand eluted with ethyl acetate/petroleum ether (1/5) to give (13 g,56.67%) of the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺368.

Step 11: Synthesis of1-methyl-6-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

To a stirred mixture of1-methyl-6-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(2 g, 5.45 mmol, 1 equiv) and2-chloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine (1.5 g, 6.53 mmol,1.2 equiv), prepared as described in Example 1 above, in dioxane (200mL) were added H₂O (40 mL), K₃PO₄ (2.3 g, 10.89 mmol, 2 equiv) andAMPhosPdCl₂ (1.2 g, 1.63 mmol, 0.3 equiv). The resulting mixture wasstirred overnight at 50° C. under nitrogen atmosphere and then dilutedwith water. The organics were extracted with EtOAc and the combinedorganic layers were concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with PE/EtOAc (3/1)to give crude product which was re-crystallized from MeOH (50 mL) toafford (706.7 mg, 29.60%) of the title compound as a yellow solid.LC-MS: (ES, m/z): [M+H]⁺ 439; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 2.35(s, 3H), 2.90-3.05 (m, 2H), 3.73-3.79 (m, 1H), 4.02-4.14 (m, 4H), 7.49(s, 1H), 7.53-7.55 (d, 1H), 8.46-8.49 (m, 2H), 8.55 (s, 1H), 8.81 (d,1H), 9.95 (s, 1H).

Example 5 Synthesis of7-(2,5-dimethyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of 4-methyl-5-nitro-2-(trifluoromethyl)pyridine

Into a 2 L 3-necked round-bottom flask under N₂ atmosphere, was placed2-bromo-4-methyl-5-nitropyridine (100 g, 460.79 mmol, 1 equiv), methyl2,2-difluoro-2-(fluorosulfonyl)acetate (177.0 g, 921.57 mmol, 2 equiv),and CuI (70.2 g, 368.60 mmol, 0.800 equiv) in DMF (1 L). The resultingsolution was stirred for 14 h at 120° C. and then diluted with NH₄Cl (3L), NH₄OH (0.5 L). The resulting solution was extracted with ethylacetate and the combined organic layer was concentrated under reducedpressure. The residue was applied onto a silica gel column and elutedwith petroleum ether to give (40 g, 41.94%) of the title compound as ared oil. GC-MS: (ES, m/z): [M]⁺206.

Step 2: Synthesis of 4-methyl-6-(trifluoromethyl)pyridin-3-amine

Into a 1 L 3-necked round-bottom flask was placed4-methyl-5-nitro-2-(trifluoromethyl)pyridine (60 g, 291.26 mmol, 1equiv), Fe (48.9 g, 873.79 mmol, 3 equiv), NH₄Cl (77.2 g, 1456.31 mmol,5 equiv), and H₂O (500 mL). The resulting mixture was stirred for 2 at80° C. The resulting solution was extracted with ethyl acetate. Theresidue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1/10) to give (27 g, 60.76%) of the titlecompound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 177.

Step 3: Synthesis of 2-bromo-4-methyl-6-(trifluoromethyl)pyridin-3-amine

To a stirred solution 4-methyl-6-(trifluoromethyl)pyridin-3-amine (27 g,153.41 mmol, 1 equiv) in DCM (270 mL) was added NBS (27.1 g, 153.41mmol, 1 equiv) in portions at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred for 2 h at 0° C. under nitrogenatmosphere. The reaction mixture was quenched with water at roomtemperature and the resulting mixture was extracted with CH₂Cl₂. Thecombined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure. Theresidue was purified by silica gel column chromatography with PE/EtOAc(30/1) as eluent to afford (36.4 g, 96.45%) of the title compound as ared solid. LC-MS: (ES, m/z): [M+H]⁺ 255.

Step 4: Synthesis of ethyl3-(3-amino-4-methyl-6-(trifluoromethyl)pyridin-2-yl)acrylate

To a stirred mixture of2-bromo-4-methyl-6-(trifluoromethyl)pyridin-3-amine (36 g, 141.16 mmol,1 equiv) and ethyl prop-2-enoate (28.3 g, 282.67 mmol, 2.00 equiv) inDMF (720 mL) were added P(o-tol)₃ (8.6 g, 28.23 mmol, 0.2 equiv), Et₃N(42.9 g, 423.47 mmol, 3 equiv) and Pd(OAc)₂ (3.2 g, 14.12 mmol, 0.1equiv). The resulting mixture was stirred overnight at 100° C. undernitrogen atmosphere. The reaction was quenched with water at roomtemperature. The resulting mixture was extracted with EtOAc and thecombined organic layers were washed with NaCl (aq.). The resultingorganic layer was concentrated under reduced pressure and the residuewas purified by silica gel column chromatography, eluted with PE/EtOAc(20/1) to afford (23.9 g, 61.74%) of the title compound as a yellowsolid. LC-MS: (ES, m/z): [M+H]⁺ 275.

Step 5: Synthesis of 8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2(1H)-one

Into a 500 mL 3-necked round-bottom flask, was placed ethyl3-(3-amino-4-methyl-6-(trifluoromethyl)pyridin-2-yl)acrylate (23.9 g,87.23 mmol, 1 equiv), 1,4-dioxane (120 mL), and HCl (6M) (120 mL). Theresulting solution was stirred overnight at 100° C. The resultingmixture was diluted with water and the solids were collected byfiltration to give (18.8 g, 94.52%) of the title compound as a greysolid. LC-MS: (ES, m/z): [M+H]⁺ 229.

Step 6: Synthesis of6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridine

Into a 250-mL 3-necked round-bottom flask, was placed8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2 (1H)-one (18.75 g, 82.24mmol, 1 equiv), benzene phosphorus oxydichloride (95 mL). The resultingsolution was heated to reflux for 3 h and then diluted with water. Thesolids were collected by filtration to give (15.7123 g, 77.67%) of thetitle compound as a grey solid. LC-MS: (ES, m/z): [M+H]⁺ 247.

Step 7. Synthesis of4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2,5-dimethylphenyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced 4-bromo-2,5-dimethylaniline (2.5 g, 12.72 mmol, 1.5 equiv), Et₃N(1.3 g, 12.72 mmol, 1.5 equiv), DCM (25 mL).4-(2-(Benzyloxy)ethoxy)-1-methyl-1H-pyrazole-5-carbonyl chloride (2.5 g,8.48 mmol, 1 equiv), prepared as described in Example 1, in 25 mL of DCMwas added dropwise at 0° C. The resulting solution was stirred for 2 hat 0° C. The resulting mixture was concentrated under vacuum and thecrude product was purified by re-crystallization from MeOH to give (3.78g, 97.23%) of the title compound as a yellow solid. LC-MS: (ES, m/z):[M+H]⁺ 458.

Step 8: Synthesis ofN-(4-bromo-2,5-dimethylphenyl)-4-(2-hydroxyethoxy)-1-methyl-1H-pyrazole-5-carboxamide

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced4-(2-(benzyloxy)-ethoxy)-N-(4-bromo-2,5-dimethylphenyl)-1-methyl-1H-pyrazole-5-carboxamide(3.78 g, 8.25 mmol, 1 equiv), DCM (40 mL), and BCl₃ (1.4 g, 12.07 mmol,1.46 equiv) was added at 0° C. The resulting solution was stirred for 30min at 0° C. and then quenched with 50 mL of NaHCO₃(aq.). The resultingsolution was extracted with dichloromethane. The combined organic layerwas dried over anhydrous sodium sulfate and concentrated under vacuum togive (3 g, 98.79%) of the title compound as a yellow solid. (ES, m/z):[M+H]⁺ 368

Step 9: Synthesis of2-((5-((4-bromo-2,5-dimethylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)oxy)ethylmethanesulfonate

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplacedN-(4-bromo-2,5-dimethylphenyl)-4-(2-hydroxyethoxy)-1-methyl-1H-pyrazole-5-carboxamide(3 g, 8.15 mmol, 1 equiv), Et₃N (1.2 g, 12.22 mmol, 1.5 equiv), DCM (30mL), and MsCl (1.4 g, 12.22 mmol, 1.5 equiv) was added dropwise at 0° C.The resulting solution was stirred for 1 h at 0° C. The reaction wasthen quenched with water and the resulting solution was extracted withdichloromethane. The combined organic layer was dried over anhydroussodium sulfate and concentrated to give (3.5 g, 96.25%) of the titlecompound as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 446.

Step 10: Synthesis of7-(4-bromo-2,5-dimethylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced2-((5-((4-bromo-2,5-dimethylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)oxy)ethylmethanesulfonate (3.7 g, 8.29 mmol, 1 equiv), DMF (40 mL), and NaH (0.3g, 12.50 mmol, 1.51 equiv) was added at 0° C. The resulting solution wasstirred for 1 h at 0° C. and then quenched with NH₄Cl (aq.). Theresulting solution was extracted with ethyl acetate. The combinedorganic layer was concentrated under reduced pressure. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/petroleumether (1:20) to give (2 g, 68.89%) of the title compound as a yellowsolid. LC-MS: (ES, m/z): [M+H]⁺ 350.

Step 11: Synthesis of7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placed7-(4-bromo-2,5-dimethylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]-oxazepin-8(5H)-one (2 g, 5.71 mmol, 1 equiv), B₂Pin₂ (2.18 g, 8.60 mmol, 1.5equiv), KOAc (1.7 g, 17.13 mmol, 3 equiv), dioxane (20 mL), andPd(dppf)Cl₂ (0.6 g, 0.86 mmol, 0.15 equiv). The resulting solution wasstirred for 12 h at 80° C. The resulting mixture was concentrated undervacuum. The residue was applied onto a silica gel column and eluted withethyl acetate/petroleum ether (1:20) to give (2.2 g, 96.97%) of thetitle compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 398.

Step 12: Synthesis of7-(2,5-dimethyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placed7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (800 mg, 2.01 mmol, 1 equiv),6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridine (595.9 mg, 2.42mmol, 1.2 equiv), Na₂CO₃ (640.3 mg, 6.04 mmol, 3 equiv), DME (14 mL),H₂O (3.5 mL), and Pd(PPh₃)₄ (349.0 mg, 0.30 mmol, 0.15 equiv). Theresulting solution was stirred for 12 h at 80° C. The reaction was thenquenched with water. The resulting solution was extracted with ethylacetate and the combined organic layer was concentrated under reducedpressure. The residue was applied onto a silica gel column and elutedwith dichloromethane/methanol (50:1) to give (529.9 mg, 54.65%) of thetitle compound as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 482. ¹H-NMR:(300 MHz, DMSO-d₆, ppm): δ 8.65 (d, 1H), 8.17 (s, 1H), 8.16 (d, 1H),7.58 (s, 1H), 7.37 (s, 1H), 7.29 (s, 1H), 4.46-4.58 (m, 2H), 3.98-4.02(m, 5H), 2.89 (s, 3H), 2.51 (s, 3H), 2.25 (s, 3H).

Example 6 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of 2-bromo-6-(trifluoromethyl)pyridin-3-amine

To a stirred solution of 6-(trifluoromethyl)pyridin-3-amine (5 g, 30.84mmol, 1 equiv) in acetonitrile (200 mL) were added NBS (5.49 g, 30.84mmol, 1 equiv) in portions at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred at 0° C. for 30 mins and then quenchedwith water. The resulting mixture was extracted with EtOAc. The combinedorganic layers were concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluted with EtOAc/PE(1/10) to afford (3.14 g, 42.24%) of the title compound as a yellowsolid. LC-MS: (ES, m/z): [M+H]⁺ 241.

Step 2: Synthesis of ethyl3-(3-amino-6-(trifluoromethyl)pyridin-2-yl)acrylate

To a stirred solution of 2-bromo-6-(trifluoromethyl)pyridin-3-amine(3.14 g, 13.03 mmol, 1 equiv) and ethyl prop-2-enoate (2.61 g, 26.06mmol, 2 equiv) in DMF (60 mL) were added Et₃N (3.95 g, 39.09 mmol, 3equiv), P(o-tol)₃ (0.40 g, 1.30 mmol, 0.1 equiv) and Pd(OAc)₂ (0.15 g,0.65 mmol, 0.05 equiv). The resulting mixture was stirred under nitrogenat 120° C. overnight. The reaction mixture was quenched with water andextracted with EtOAc. The combined organic layers were concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography and eluted with EtOAc/PE (1/5) to afford (3.3 g, 97.34%)of the title compound as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 261.

Step 3: Synthesis of 6-(trifluoromethyl)-1,5-naphthyridin-2 (1H)-one

To a stirred solution of ethyl3-(3-amino-6-(trifluoromethyl)pyridin-2-yl)acrylate (1.5 g, 5.76 mmol, 1equiv) in 1,4-dioxane (15 mL) was added HCl (30 mL). The resultingmixture was stirred at 100° C. overnight. The reaction mixture wasbasified to pH 8 with saturated NaHCO₃ and extracted with EtOAc. Thecombined organic layers were concentrated under reduced pressure to givethe title compound (1.1 g, 89.11%) as a yellow solid. LC-MS: (ES, m/z):[M+H]⁺ 215.

Step 4: Synthesis of 2-chloro-6-(trifluoromethyl)-1,5-naphthyridine

A solution of 6-(trifluoromethyl)-1,5-naphthyridin-2 (1H)-one (1.18 g,5.51 mmol, 1 equiv) in POCl₃ (12 mL, 128.74 mmol, 23.364 equiv) wasstirred at 120° C. for 30 min. The reaction mixture was quenched withwater/ice and then basified to pH 8 with saturated NaHCO₃. The resultingmixture was extracted with EtOAc. The combined organic layers wereconcentrated under reduced pressure to give (900 mg, 70.22%) of thetitle compound as a grey solid.

Step 5: Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, was placed2-chloro-6-(trifluoromethyl)-1,5-naphthyridine (500 mg, 2.15 mmol, 1equiv),3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (789.5 mg, 2.15 mmol, 1.00 equiv), prepared as described inExample 2 above, Na₂CO₃ (683.5 mg, 6.45 mmol, 3 equiv), DME (10 mL,103.32 mmol, 48.06 equiv), H₂O (2.5 mL, 138.77 mmol, 64.55 equiv), andPd(PPh₃)₄ (372.6 mg, 0.32 mmol, 0.15 equiv). The resulting solution wasstirred for 12 h at 80° C. The reaction was then quenched with water andthe resulting solution was extracted with ethyl acetate. Afterconcentration of the organic layer, the residue was applied onto asilica gel column and eluted with dichloromethane/methanol (20/1) togive (601.5 mg, 63.97%) of the title compound as a yellow solid. LC-MS:(ES, m/z): [M+H]⁺ 438; ¹H-NMR: (300 MHz, DMSO, ppm): δ 2.27 (s, 3H),2.35 (s, 3H), 3.90-3.94 (m, 1H), 4.26-4.35 (m, 1H), 4.51-4.55 (t, 2H),7.48 (s, 1H), 7.56 (d, 1H), 8.25 (dd, 2H), 8.33 (s, 1H), 8.61 (d, 1H),8.69 (d, 1H), 8.79 (d, 1H).

Example 7 Synthesis of5-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of ethyl1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylate

To a stirred solution of ethyl 4-methyl-1H-pyrazole-5-carboxylate (50 g,324.32 mmol, 1 equiv), DIAD (137.7 g, 681.07 mmol, 2.1 equiv) and2-(benzyloxy)ethan-1-ol (49.4 g, 324.59 mmol, 1 equiv) in THF (500 mL)was added PPh₃ (221.2 g, 843.23 mmol, 2.6 equiv) in portions at 0° C.under nitrogen atmosphere. The resulting mixture was stirred overnightat room temperature. The residue was purified by silica gel columnchromatography with PE/EtOAc (50/1) as eluent to afford the titlecompound (73 g, 78.06%) as a yellow oil. LC-MS: (ES, m/z): [M+H]⁺ 289.Ethyl 1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylate wasconverted to 1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylicacid as described in Example 2, Step 5 above.

Step 2: Synthesis of1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carbonyl chloride

To a stirred solution of1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylic acid (15 g,57.63 mmol, 1 equiv) and DMF (0.4 g, 5.76 mmol, 0.1 equiv) in DCM (300mL) was added (COCl)₂ (11.0 g, 86.44 mmol, 1.5 equiv) dropwise at 0° C.The resulting mixture was stirred for 3 h at room temperature and then.concentrated under reduced pressure to give the title compound (17 g,crude) as a white solid.

Step 3: Synthesis of1-(2-(benzyloxy)ethyl)-N-(4-bromo-2-fluoro-5-methylphenyl)-4-methyl-1H-pyrazole-5-carboxamide

To a stirred solution of 4-bromo-2-fluoro-5-methylaniline (18.4 g, 90.41mmol, 1.2 equiv) and Et₃N (15.2 g, 150.68 mmol, 2 equiv) in DCM (200 mL)was added 1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carbonylchloride (21 g, 75.34 mmol, 1 equiv) dropwise at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 1 h at RT undernitrogen atmosphere and then diluted with water. The aqueous layer wasextracted with CH₂Cl₂ and the organics were concentrated under reducedpressure. The crude product was re-crystallized from MeOH to afford (26g, 77.32%) of the title compound as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 446.

Step 4: Synthesis ofN-(4-bromo-2-fluoro-5-methylphenyl)-1-(2-hydroxyethyl)-4-methyl-1H-pyrazole-5-carboxamide

By proceeding analogously as described in Example 3, Step 3 above, butsubstituting1-(2-(benzyloxy)ethyl)-N-(4-bromo-2-fluoro-5-methylphenyl)-4-methyl-1H-pyrazole-5-carboxamide(26 g, 58.25 mmol, 1 equiv) for1-(2-(benzyloxy)ethyl)-N-(4-bromo-2,5-dimethylphenyl)-4-methyl-1H-pyrazole-5-carboxamide,(19.1 g, 95.82%) of the title compound was obtained as a white solid.LC-MS: (ES, m/z): [M+H]⁺ 356.

Step 5: Synthesis of2-(5-((4-bromo-2-fluoro-5-methylphenyl)carbamoyl)-4-methyl-1H-pyrazol-1-yl)ethylmethanesulfonate

To a stirred solution ofN-(4-bromo-2-fluoro-5-methylphenyl)-1-(2-hydroxyethyl)-4-methyl-1H-pyrazole-5-carboxamide(19.1 g, 53.62 mmol, 1 equiv) and Et₃N (10.9 g, 107.24 mmol, 2 equiv) inDCM (190 mL) was added MsCl (9.2 g, 80.43 mmol, 1.5 equiv) dropwise at0° C. The resulting mixture was stirred for 30 min at room temperatureand then diluted with water. The resulting mixture was extracted withCH₂Cl₂ and the combined organic layers were dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressure.The crude product was re-crystallized from EA to afford (20.5 g, 88.03%)of the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 434.

Step 6: Synthesis of5-(4-bromo-2-fluoro-5-methylphenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution of2-(5-((4-bromo-2-fluoro-5-methylphenyl)carbamoyl)-4-methyl-1H-pyrazol-1-yl)ethylmethanesulfonate (20.9 g, 48.13 mmol, 1 equiv) in DMF (209 mL) was addedNaH (60%)(2.9 g, 72.19 mmol, 1.5 equiv) at 0° C. under nitrogenatmosphere. The resulting mixture was stirred for 0.5 h at 0° C. undernitrogen atmosphere. The reaction mixture was quenched by the additionof sat.NH₄Cl (aq.) (200 mL) at room temperature. The resulting mixturewas extracted with EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure to give the title compound (16.2 g, 99.54%) as a whitesolid. LC-MS: (ES, m/z): [M+H]⁺ 338.

Step 7: Synthesis of5-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution of5-(4-bromo-2-fluoro-5-methylphenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (16.1 g, 47.61 mmol, 1 equiv) and B₂Pin₂ (18.1 g, 71.41 mmol,1.5 equiv) in dioxane (161 mL) were added KOAc (9.3 g, 95.22 mmol, 2equiv) and Pd(dppf)Cl₂ (3.5 g, 4.76 mmol, 0.1 equiv). The resultingmixture was stirred overnight at 80° C. under nitrogen atmosphere. Theresulting mixture was concentrated under reduced pressure. The residuewas purified by silica gel column chromatography with PE/EtOAc (5/1) aseluent to afford the title compound (15.8 g, 86.15%) as a white solid.LC-MS: (ES, m/z): [M+H]⁺ 386.

Step 8: Synthesis of5-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution of 2-chloro-6-(trifluoromethyl)-1,5-naphthyridine(500 mg, 2.15 mmol, 1 equiv) and5-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (828.2 mg, 2.15 mmol, 1 equiv) in DME (10 mL) and H₂O (2.5 mL)was added Na₂CO₃ (683.5 mg, 6.45 mmol, 3 equiv) and Pd(PPh₃)₄ (248.4 mg,0.21 mmol, 0.1 equiv). The resulting mixture was stirred overnight at80° C. under nitrogen atmosphere. The reaction mixture was diluted withwater at room temperature and the resulting mixture was extracted withEtOAc. The combined organic layers were concentrated under reducedpressure and the residue was purified by silica gel columnchromatography, eluted with PE/EtOAc (1/2) to afford the title compound(701.3 mg, 71.63%) as a grey solid. LC-MS: (ES, m/z): [M+H]⁺ 456.¹H-NMR: (400 MHz, DMSO-d₆, ppm): (400 MHz, DMSO, ppm): δ 2.27 (s, 3H),2.43 (s, 3H), 4.18 (t, 2H), 4.52 (t, 2H), 7.50 (s, 1H), 7.55 (d, 1H),7.61 (d, 1H), 8.21 (d, 1H), 8.29 (d, 1H), 8.72 (d, 1H), 8.79 (d, 1H).

Example 8 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinolin-2-yl)phenyl)-6,7-dihydropyrazolo-[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of ethyl 3-(2-amino-5-(trifluoromethyl)phenyl)acrylate

Proceeding analogously as described in Example 6, Step 2 above butsubstituting 2-bromo-6-(trifluoromethyl)pyridin-3-amine with2-bromo-4-trifluoromethylaniline provided (34 g, 92.27%) of the titlecompound as a yellow solid LC-MS: (ES, m/z): [M+H]⁺ 260.

Step 2: Synthesis of 6-(trifluoromethyl)quinolin-2 (1H)-one

Into a 2 L round-bottom flask, was placed ethyl3-(2-amino-5-(trifluoromethyl)phenyl)-acrylate (34 g, 131.27 mmol, 1.00equiv), dioxane (340 mL), and HCl (4M) (340 mL). The resulting solutionwas stirred for 12 h at 100° C. and then quenched with H₂O. Theresulting solution was extracted with ethyl acetate. The combinedorganic layers were dried over anhydrous sodium sulfate andconcentrated. The crude product was purified by re-crystallization fromPE/EA (10/1) to give (27 g, 96.57%) of the title compound as a whitesolid. LC-MS: (ES, m/z): [M+H]⁺ 214.

Step 3: Synthesis of 2-chloro-6-(trifluoromethyl)quinoline

Into a 500-mL 3-necked round-bottom flask was placed6-(trifluoromethyl)quinolin-2 (1H)-one (31 g, 145.54 mmol, 1.00 equiv),and POCl₃ (155 mL). The resulting solution was stirred for 3 h at 120°C. The resulting mixture was concentrated under vacuum. The residue wasthen quenched with water/ice and extracted with ethyl acetate. Themixture was dried over anhydrous sodium sulfate and concentrated to give(28 g, 83.28%) of the title compound as a tan solid. LC-MS: (ES, m/z):[M+H]⁺ 232.

Step 4: Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred mixture of3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (1 g, 2.72 mmol, 1 equiv) and2-chloro-6-(trifluoromethyl)quinoline (632 mg, 2.72 mmol, 1.00 equiv) inDME (12.64 mL) were added Na₂CO₃ (866.5 mg, 8.18 mmol, 3.00 equiv),Pd(PPh₃)₄ (314.4 mg, 0.27 mmol, 0.10 equiv) and H₂O (3.16 mL, 175.41mmol, 64.42 equiv). The resulting solution was stirred for 3 h at 80° C.under nitrogen atmosphere. The reaction mixture was diluted with 50 mLof water and extracted with EtOAc. The combined organic layer wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with PE/EtOAc (5/1) as eluent to afford thetitle compound (0.7792 g, 65.57%) as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 437. ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 2.26 (s, 3H), 2.35 (s,3H), 3.90-3.94 (m, 1H), 4.26-4.33 (m, 1H), 4.51-4.54 (t, 2H), 7.48 (s,1H), 7.54 (d, 1H), 8.02 (dd, 1H), 8.21 (dd, 1H), 8.27-8.29 (m, 2H), 8.35(d, 1H), 8.54 (s, 1H), 8.69 (d, 1H).

Example 9 Synthesis of3-methyl-5-(2-methyl-4-(8-methyl-6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of 2-methyl-4-(trifluoromethyl)aniline

To a stirred mixture of 2-bromo-4-(trifluoromethyl)aniline (100 g,416.63 mmol, 1 equiv) and trimethyl-1,3,5,2,4,6-trioxatriborinane (210.2g, 1674.50 mmol, 4.02 equiv) in DMF were added Pd(PPh₃)₄ (24.2 g, 20.94mmol, 0.05 equiv) and K₂CO₃ (144.4 g, 1044.82 mmol, 2.51 equiv). Theresulting mixture was stirred overnight at 100° C. under nitrogenatmosphere. The reaction was diluted with water and extracted withEtOAc. The combined organic layer was concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith PE/EtOAc (10:1) as eluent to afford the title compound (60 g,81.94%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 176.

Step 2: Synthesis of 2-bromo-6-methyl-4-(trifluoromethyl)aniline

To a stirred solution of 2-methyl-4-(trifluoromethyl)aniline (60 g,342.86 mol, 1 equiv) in DCM (1200 mL) was added NBS (60.7 g, 342.86mmol, 1 equiv) in portions at 0° C. under nitrogen atmosphere. Theresulting mixture was stirred for 2 h at 0° C. under nitrogenatmosphere. The reaction mixture was quenched with water at roomtemperature. The aqueous layer was extracted with DCM and the combinedorganic layers were concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with PE/EtOAc (30/1) aseluent to afford the title compound (49 g, 67.57%) as yellow oil. LC-MS:(ES, m/z): [M+H]⁺ 254.

Step 3: Synthesis of 2-amino-3-methyl-5-(trifluoromethyl)benzonitrile

To a stirred solution of 2-bromo-6-methyl-4-(trifluoromethyl)aniline (49g, 193.68 mol, 1 equiv) and Zn(CN)₂ (44.9 g, 141.34 mmol, 2.00 equiv) inDMF (1000 mL) was added Pd(PPh₃)₄ (11.2 g, 9.68 mmol, 0.05 equiv) atroom temperature under nitrogen atmosphere. The resulting mixture wasstirred overnight at 120° C. under nitrogen atmosphere. The reaction wasquenched with water at room temperature and the aqueous layer wasextracted with EtOAc. The combined organic layers were concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography with PE/EtOAc (10/1) as eluent to afford the titlecompound (37.6 g, 97.16%) as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺201.

Step 4: Synthesis of 8-methyl-6-(trifluoromethyl)quinazoline-2.4(1H,3H)-dione

To a stirred mixture of 2-amino-3-methyl-5-(trifluoromethyl)benzonitrile(37.6 g, 188.00 mmol, 1 equiv) in DMF (1200 mL) were added DBU (139.3 g,564.00 mmol, 3.00 equiv). The resulting mixture was stirred overnight at100° C. under CO₂ atmosphere. The reaction was quenched with water atroom temperature. The mixture was acidified to pH5 with HCl (5M). Theprecipitated solids were collected by filtration and washed with water.The resulting solid was dried under infrared light to give the titlecompound (40 g, 87.20%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 245.

Step 5: Synthesis of2,4-dichloro-8-methyl-6-(trifluoromethyl)quinazoline

To a stirred mixture of 8-methyl-6-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (29 g, 118.85 mmol, 1 equiv) in POCl₃ (150 mL) was addedPCl₅ (123.6 g, 594.26 mmol, 5 equiv). The resulting mixture was stirredfor 8 hours at 120° C. under nitrogen atmosphere. The resulting mixturewas concentrated under vacuum and the residue was quenched withwater/ice at room temperature. The aqueous layer was extracted with MTBEand the combined organic layers were washed with H₂O. The resultingorganic phase was dried with anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography with PE/EtOAc (100/1) as eluent to afford the titlecompound (15.5 g, 46.57%) as a white solid. GC-MS: (ES, m/z): [M]⁺280.

Step 6: Synthesis of 2-chloro-8-methyl-6-(trifluoromethyl)quinazoline

To a stirred mixture of2,4-dichloro-8-methyl-6-(trifluoromethyl)quinazoline (34.8 g, 124.28mmol, 1 equiv) in THF (350 mL) was added Bn₃SnH (39.9 g, 136.93 mmol,1.10 equiv). Pd(PPh₃)₄ (14.4 g, 12.43 mmol, 0.10 equiv) was added at 0°C. under nitrogen atmosphere. The resulting mixture was stirredovernight at room temperature under nitrogen atmosphere. The reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography, eluted with PE/EtOAc(100/1) to afford the title compound (15.1308 g, 49.49%) as a lightyellow solid. GC-MS: (ES, m/z): [M]⁺246.

Step 7: Synthesis of3-methyl-5-(2-methyl-4-(8-methyl-6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution of3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (1.2 g, 3.27 mmol, 1 equiv) and2-chloro-8-methyl-6-(trifluoromethyl)quinazoline (0.8 g, 3.27 mol, 1.00equiv) in toluene (24 mL) was added EtOH (12 mL), K₂CO₃ (1.4 g, 9.80mmol, 3 equiv) and Pd(PPh₃)₄ (0.4 g, 0.33 mmol, 0.1 equiv). Theresulting mixture was stirred overnight at 80° C. under nitrogenatmosphere. The resulting mixture was diluted with and extracted withEtOAc. The combined organic layer was concentrated under reducedpressure. The residue was purified by silica gel column chromatographywith PE/EtOAc (1/1) as eluent to the title compound (661 mg, 44.81%) asa white solid. LC-MS: (ES, m/z): [M+H]⁺ 452. ¹H-NMR: (300 MHz, DMSO-d₆,ppm): δ 2.21 (s, 3H), 2.36 (s, 3H), 2.88 (s, 3H), 3.90-3.93 (m, 1H),4.27-4.33 (m, 1H), 4.53 (t, 2H), 7.48 (s, 1H), 7.56 (d, 1H), 8.17 (s,1H), 8.50-8.60 (m, 3H), 9.86 (s, 1H).

Example 10 Synthesis of6-(2,5-dimethyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Step 1: Synthesis of methyl 4-allyl-1-methyl-1H-pyrazole-5-carboxylate

Into a 250-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced methyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (5 g, 22.83mmol, 1 equiv), tributyl(prop-2-en-1-yl)stannane (8.3 g, 25.07 mmol,1.10 equiv), DMF (50 mL), Pd(PPh₃)₄ (2.6 g, 2.25 mmol, 0.10 equiv). Theresulting solution was stirred overnight at 100° C. The reaction mixturewas then quenched with water and extracted with ethyl acetate and theorganic layers combined. The resulting mixture was concentrated and theresidue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:50) to give (3.2 g, 77.79%) of the titlecompound as yellow oil. LC-MS: (ES, m/z): [M+H]⁺ 181.

Step 2: Synthesis of 4-allyl-1-methyl-1H-pyrazole-5-carboxylic acid

Into a 50-mL 3-necked round-bottom flask, was placed methyl4-allyl-1-methyl-1H-pyrazole-5-carboxylate (3.2 g, 17.76 mmol, 1 equiv),THF (15 mL, 185.14 mmol, 10.43 equiv), and LiOH (0.9 g, 37.58 mmol, 2.12equiv) in H₂O (7 mL). The resulting solution was stirred overnight atroom temperature and then diluted with H₂O. The resulting mixture wasconcentrated and the resulting solution was extracted with ethylacetate. The pH value of the aqueous layer was adjusted to 4 with HCl (1mol/L) and the organics were extracted with ethyl acetate. The combinedorganic layer was dried over anhydrous sodium sulfate and concentratedunder reduced pressure to give (2.1 g, 71.16%) of the title compound asa white solid. GC-MS: (ES, m/z): [M]⁺166.

Step 3: Synthesis of4-allyl-N-(4-bromo-2,5-dimethylphenyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, was placed4-allyl-1-methyl-1H-pyrazole-5-carboxylic acid (0.843 g, 5.07 mmol, 1equiv), 4-bromo-2,5-dimethylaniline (1.0 g, 5.00 mmol, 0.99 equiv), HATU(2.9 g, 7.63 mmol, 1.50 equiv), DIEA (1.3 g, 10.15 mmol, 2 equiv) andDMF (10 mL). The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched with water and the resultingsolution was extracted with ethyl acetate. The combined organic layerwas concentrated under reduced pressure. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1:10)to give 1.2 g (67.93%) of title compound as a white solid. LC-MS: (ES,m/z): [M+H]⁺ 348.

Step 4: Synthesis ofN-(4-bromo-2,5-dimethylphenyl)-4-(2,3-dihydroxypropyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placed4-allyl-N-(4-bromo-2,5-dimethylphenyl)-1-methyl-1H-pyrazole-5-carboxamide(1.2 g, 3.45 mmol, 1 equiv), THF (12 mL, 148.12 mmol, 42.98 equiv), NMO(1.2 g, 10.24 mmol, 2.97 equiv), H₂O (6 mL), and OsO₄ (43.8 mg, 0.17mmol, 0.05 equiv). The resulting solution was stirred for 4 at roomtemperature and then quenched with 50 mL NaS₂O₈(aq.). The resultingsolution was extracted with ethyl acetate. The combined organic layerwas washed with H₂O, dried over anhydrous sodium sulfate andconcentrated under vacuum to give 1.41 g of the title compound as acrude product. LC-MS: (ES, m/z): [M+H]⁺ 382.

Step 5: Synthesis ofN-(4-bromo-2,5-dimethylphenyl)-1-methyl-4-(2-oxoethyl)-1H-pyrazole-5-carboxamide

Into a 50-mL 3-necked round-bottom flask purged was placedN-(4-bromo-2,5-dimethylphenyl)-4-(2,3-dihydroxypropyl)-1-methyl-1H-pyrazole-5-carboxamide(1.41 g, 3.69 mmol, 1 equiv), MeOH (15 mL), H₂O (1.5 mL), and NaIO₄ (1.6g, 7.48 mmol, 2.03 equiv). The resulting solution was stirred for 2 h atroom temperature and then quenched with H₂O. The resulting mixture wasconcentrated to remove MeOH and the resulting solution was extractedwith ethyl acetate. The combined organic layer was washed with H₂O,dried over anhydrous sodium sulfate and concentrated under reducedpressure to give (1.2 g, 92.89%) the title compound as a solid. LC-MS:(ES, m/z): [M+H]⁺ 350.

Step 6: Synthesis ofN-(4-bromo-2,5-dimethylphenyl)-4-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placedN-(4-bromo-2,5-dimethylphenyl)-1-methyl-4-(2-oxoethyl)-1H-pyrazole-5-carboxamide(1.2 g, 3.43 mmol, 1 equiv), MeOH (12 mL, 296.39 mmol, 86.50 equiv).NaBH₄ (0.2 g, 5.29 mmol, 1.54 equiv) was added at 0° C. The resultingsolution was stirred for 2 h at RT and then quenched with NH₄Cl (aq.).The resulting solution was extracted with ethyl acetate. The combinedorganic layer was washed with H₂O, dried over anhydrous sodium sulfateand concentrated under reduced pressure to give (1.22 g) the titlecompound as crude product. LC-MS: (ES, m/z): [M+H]⁺ 352.

Step 7: Synthesis of2-(5-((4-bromo-2,5-dimethylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)ethylmethanesulfonate

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placedN-(4-bromo-2,5-dimethylphenyl)-4-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide(1.3 g, 3.69 mmol, 1 equiv), DCM (15 mL), Et₃N (0.7 g, 6.92 mmol, 1.87equiv). MsCl (0.6 g, 5.24 mmol, 1.42 equiv) was added dropwise at 0° C.The resulting solution was stirred for 2 h at room temperature. Thereaction was then quenched with 50 mL of NaHCO₃(aqu.). The resultingsolution was extracted with ethyl acetate and the organic layerscombined. The resulting mixture was washed with H₂O, dried overanhydrous sodium sulfate and concentrated under vacuum to give 1.41 g ofthe title compound as a crude product. LC-MS: (ES, m/z): [M+H]⁺ 430.

Step 8: Synthesis of6-(4-bromo-2,5-dimethylphenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placed2-(5-((4-bromo-2,5-dimethylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)ethylmethanesulfonate (1.41 g, 3.28 mmol, 1 equiv), DMF (15 mL). NaH (0.1 g,4.17 mmol, 1.27 equiv) was added at 0° C. The resulting solution wasstirred for 2 at room temperature. The reaction was then quenched by theaddition of 50 mL of NH₄Cl (aq.). The resulting solution was extractedwith ethyl acetate and the organic layers combined. The resultingmixture was washed with H₂O. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:5) to give (843mg, 76.98%) of the title compound as a white solid. LC-MS (ES, m/z):[M+H]⁺ 334.

Step 9: Synthesis of1-methyl-6-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placed6-(4-bromo-2,5-dimethylphenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(843 mg, 2.52 mmol, 1 equiv), dioxane (10 mL), KOAc (742.6 mg, 7.57mmol, 3 equiv), and Pd(dppf)Cl₂ (553.7 mg, 0.76 mmol, 0.30 equiv). Theresulting solution was stirred for overnight at 80° C. The resultingmixture was concentrated under vacuum. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1:5) togive (520 mg, 54.07%) of the title compound as a white solid. LC-MS:(ES, m/z): [M+H]⁺ 382.

Step 10: Synthesis of6-(2,5-dimethyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Proceeding analogously as described in Example 7, Step 8 above, butsubstituting5-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one with1-methyl-6-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-onegave (300 mg, 63.34%) of the title compound as a white solid. LC-MS:(ES, m/z): [M+H]⁺ 452; ¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 8.77 (d, 1H),8.69 (d, 1H), 8.27 (d, 1H), 8.17 (d, 1H), 7.55 (s, 1H), 7.48 (s, 1H),7.34 (s, 1H), 4.01-4.09 (m, 4H), 3.71-3.79 (m, 1H), 2.90-3.04 (m, 2H),2.40 (s, 3H), 2.25 (s, 3H).

Example 11 Synthesis of6-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Step 1: Synthesis of 4-allyl-1-methyl-1H-pyrazole-5-carboxylic acid

To a stirred solution of methyl4-allyl-1-methyl-1H-pyrazole-5-carboxylate (5.5 g, 30.52 mmol, 1 equiv)in CH₃OH (55 mL) was added NaOH (2.45 g, 61.25 mmol, 2.01 equiv) at roomtemperature under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure. The residue was acidified to pH 6with HCl (aq.). The resulting mixture was filtered and the filter cakewas washed with water. The aqueous layer was extracted with EtOAc andthe combined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure to givethe title compound (4.5 g, 88.72%) as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 167.

Methyl 4-allyl-1-methyl-1H-pyrazole-5-carboxylate was converted to4-allyl-1-methyl-1H-pyrazole-5-carbonyl chloride as described in Example4, Step 3 above.

Step 2: Synthesis of4-allyl-N-(4-bromo-2-fluoro-5-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamide

Proceeding analogously as described in Example 4, Step 4, butsubstituting 4-bromo-2-methylaniline with4-bromo-2-fluoro-5-methylaniline provided the title compound (68.49%yield) as a pink solid. LC-MS: (ES, m/z): [M+H]⁺ 352, 354.

Step 3: Synthesis ofN-(4-bromo-2-fluoro-5-methylphenyl)-4-(2,3-dihydroxypropyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 100 mL 3-necked round-bottom flask were added4-allyl-N-(4-bromo-2-fluoro-5-methyl-phenyl)-1-methyl-1H-pyrazole-5-carboxamide(3.92 g, 11.13 mmol, 1 equiv), THF (39.2 mL), H₂O (3.92 mL), NMO (3.9 g,33.39 mmol, 3.00 equiv) and OsO₄ (0.1 g, 0.39 mmol, 0.04 equiv). Theresulting mixture was stirred for 4 h at room temperature and thenquenched with Na₂S₂O₄ (aq.). The aqueous layer was extracted with EtOAc,and the resulting mixture was concentrated under reduced pressure toafford the title compound (4.5 g, 104.69%) as a white solid. The crudeproduct was used in the next step directly without further purification.LC-MS: (ES, m/z): [M+H]⁺ 386, 388.

Step 4: Synthesis ofN-(4-bromo-2-fluoro-5-methylphenyl)-4-(2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 100 mL 3-necked round-bottom flask were addedN-(4-bromo-2-fluoro-5-methylphenyl)-4-(2,3-dihydroxypropyl)-1-methyl-1H-pyrazole-5-carboxamide(4.5 g, 11.65 mmol, 1 equiv), MeOH (41 mL), H₂O (41 mL) and NaIO₄ (5.0g, 23.38 mmol, 2.01 equiv). The resulting mixture was stirred for 3 h atroom temperature and then diluted with water. The resulting mixture wasconcentrated under reduced pressure. The aqueous layer was extractedwith EtOAc and the organic layer was concentrated to afford the titlecompound (2.83 g, 68.58%) as a yellow solid. The crude product was usedin the next step directly without further purification. LC-MS: (ES,m/z): [M+H]⁺ 354, 356.

Step 5: Synthesis ofN-(4-bromo-2-fluoro-5-methylphenyl)-4-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 50 mL 3-necked round-bottom flask were addedN-(4-bromo-2-fluoro-5-methylphenyl)-4-(2-oxoethyl)-1-methyl-1H-pyrazole-5-carboxamide(2.83 g, 7.99 mmol, 1 equiv), MeOH (28.3 mL) and NaBH₄ (0.4 g, 10.57mmol, 1.32 equiv) was added at 0° C. The resulting mixture was stirredfor 3 h at room temperature under nitrogen atmosphere. The reaction wasquenched by the addition of sat. NH₄Cl (aq.) (40 mL) and the resultingmixture was concentrated under reduced pressure. The aqueous layer wasextracted with EtOAc and the organic layer was concentrated underreduced pressure. The residue was purified by silica gel columnchromatography with PE/EtOAc (1:1) as eluent to afford the titlecompound (1.3 g, 45.68%) as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺356, 358.

Step 6. Synthesis of2-(5-((4-bromo-2-fluoro-5-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)ethylmethanesulfonate

Into a 50 mL 3-necked round-bottom flask containingN-(4-bromo-2-fluoro-5-methylphenyl)-4-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide(1.3 g, 3.65 mmol, 1 equiv), and DCM (26 mL), Et₃N (0.6 g, 5.47 mmol,1.50 equiv) MsCl (0.6 g, 5.24 mmol, 1.44 equiv) was added at 0° C. Theresulting mixture was stirred for 2 h at room temperature and thendiluted with water. The aqueous layer was extracted with CH₂Cl₂ and theorganic layer was concentrated under vacuum to afford the title compound(1.75 g, 110.41%) as a yellow solid. The crude product was used in thenext step directly without further purification. LC-MS: (ES, m/z):[M+H]⁺ 434, 436.

Step 7: Synthesis of6-(4-bromo-2-fluoro-5-methylphenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Proceeding as described in Example 4, Step 9, but substituting2-(5-((4-bromo-2-fluoro-5-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)ethylmethanesulfonate for2-(5-((4-bromo-2-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)ethylmethanesulfonate the title compound was obtained (1.0 g, 73.38%) as alight yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 338, 340.

Step 8: Synthesis of6-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Proceeding as described in Example 4, Step 10 above, but substituting6-(4-bromo-2-fluoro-5-methylphenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-onefor6-(4-bromo-2-methylphenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(1.01 g, 98.51%) of the title compound was obtained as a light yellowsolid. LC-MS: (ES, m/z): [M+H]⁺ 386.

Step 9: Synthesis of6-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Into a 50 mL 3-necked round-bottom flask were added6-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(1 g, 2.60 mmol, 1 equiv),2-chloro-6-(trifluoromethyl)-1,5-naphthyridine (0.6 g, 2.58 mmol, 0.99equiv), Na₂CO₃ (0.8 g, 7.79 mmol, 3 equiv), DME (20 mL), H₂O (5 mL) andPd(PPh₃)₄ (0.3 g, 0.26 mmol, 0.1 equiv). The resulting mixture wasstirred for overnight at 80° C. under nitrogen atmosphere. The resultingmixture was concentrated under vacuum and the residue was purified bysilica gel column chromatography, eluted with PE/EtOAc (1:1) to affordthe title compound (596.1 mg, 50.43%) as a white solid. LC-MS: (ES,m/z): [M+H]⁺ 456; ¹H-NMR: (300 MHz, DMSO, ppm): δ 2.5 (s, 3H), 2.9 (t,2H), 3.9 (t, 2H), 4.09 (s, 3H), 7.5 (m, 2H), 7.6 (m, 1H), 8.2 (d, 1H),8.3 (d, 1H), 8.7 (d, 1H), 8.8 (d, 1H).

Example 12 Synthesis of7-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-fluoro-5-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamide

To a stirred solution of4-(2-(benzyloxy)ethoxy)-1-methyl-1H-pyrazole-5-carbonyl chloride (0.9 g,3.05 mmol, 1 equiv) and 4-bromo-2-fluoro-5-methylaniline (0.6 g, 3.05mmol, 1 equiv) in DCM was added Et₃N (0.5 g, 4.58 mmol, 1.5 equiv) at 0°C. under nitrogen atmosphere. The resulting solution was stirred for 30min. The reaction was quenched with water at room temperature. Theaqueous layer was extracted with CH₂Cl₂ and the organic layer wasconcentrated under reduced pressure to give the title compound (1 g,70.84%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 462.

Step 2. Synthesis ofN-(4-bromo-2-fluoro-5-methylphenyl)-4-(2-hydroxyethoxy)-1-methyl-1H-pyrazole-5-carboxamide

To a stirred solution of4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-fluoro-5-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamide(1 g, 2.16 mmol, 1 equiv) in DCM was added BCl₃ (0.5 g, 4.27 mmol, 1.98equiv) at 0° C. under nitrogen atmosphere. The resulting solution wasstirred for 3 h. The reaction was quenched with water at roomtemperature. The aqueous layer was extracted with DCM and the resultingmixture was concentrated under reduced pressure to give the titlecompound (0.8 g, 99.37%) as a light yellow solid. LC-MS: (ES, m/z):[M+H]⁺ 372.

Step 3: Synthesis of2-((5-((4-bromo-2-fluoro-5-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)oxy)ethylmethanesulfonate

To a stirred solution ofN-(4-bromo-2-fluoro-5-methylphenyl)-4-(2-hydroxyethoxy)-1-methyl-1H-pyrazole-5-carboxamide(800 mg, 2.15 mmol, 1 equiv) in DCM was added Et₃N (327 mg, 3.23 mmol,1.50 equiv) and MsCl (369 mg, 3.22 mmol, 1.50 equiv) was added at 0° C.under nitrogen atmosphere. The reaction mixture was quenched with waterat room temperature. The aqueous layer was extracted with DCM and thecombined organic layers were dried over anhydrous Na₂SO₄. Afterfiltration, the filtrate was concentrated under reduced pressure to givethe title compound (950 mg, 98.16%) as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 450.

Step 4: Synthesis of7-(4-bromo-2-fluoro-5-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

To a stirred solution of2-((5-((4-bromo-2-fluoro-5-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)oxy)ethylmethanesulfonate_(950 mg, 2.11 mmol, 1 equiv) in DMF (19 mL) was addedNaH (127 mg, 5.29 mmol, 1.5 equiv) at 0° C. The reaction was quenchedwith NH₄Cl(aq.) at room temperature and the resulting mixture wasextracted with EtOAc. The combined organic layers were concentratedunder reduced pressure to give the title compound (618 mg, 82.70%) as alight yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 354.

Step 5: Synthesis of1-methyl-7-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

To a stirred solution of7-(4-bromo-2-fluoro-5-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (618 mg, 1.74 mmol, 1 equiv) in dioxane was added KOAc (342 mg,3.48 mmol, 2.00 equiv), B2Pin2 (665 mg, 2.62 mmol, 1.50 equiv) andPd(dppf)Cl₂ (128 mg, 0.17 mmol, 0.10 equiv) and the reaction mixture washeated at 80° C. under nitrogen atmosphere. The resulting mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography with PE/EtOAc (10:1) as eluent toafford the title compound (714 mg, 101.98%) as a white solid. LC-MS:(ES, m/z): [M+H]⁺ 402.

Step 6: Synthesis of7-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

To a stirred solution of1-methyl-7-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (714 mg, 1.78 mmol, 1 equiv) and2-chloro-6-(trifluoromethyl)-1,5-naphthyridine (415 mg, 1.78 mmol, 1.00equiv) in DME (14.3 mL) were added Pd(PPh₃)₄ (205.8 mg, 0.18 mmol, 0.10equiv), Na₂CO₃ (566 mg, 5.34 mmol, 3.00 equiv) and H₂O (3.6 mL) at 80°C. under nitrogen atmosphere. The reaction was quenched by the additionof water at room temperature. The aqueous layer was extracted with EtOAcand the combined organic layers were concentrated under reducedpressure. The residue was purified by silica gel column chromatography,with PE/EtOAc (5/1) as eluent to afford the title compound (0.4245 g,50.60%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 472; ¹H-NMR: (300MHz, CDCl₃, ppm): δ 2.43 (s, 3H), 4.00 (t, 2H), 4.16 (s, 3H), 4.51-4.53(t, 2H), 7.26-7.32 (m, 2H), 7.40-7.44 (d, 1H), 7.87-7.90 (d, 1H),8.02-8.04 (d, 1H), 8.60-8.65 (m, 2H).

Example 13 Synthesis of5-(2-fluoro-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of ethyl1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylate

To a stirred solution of ethyl 4-methyl-1H-pyrazole-5-carboxylate (50 g,324.32 mmol, 1 equiv) and 2-(benzyloxy)ethan-1-ol (49.4 g, 324.59 mmol,1.00 equiv) in THF (500 mL) were added DIAD (137.7 g, 681.07 mmol, 2.1equiv) and PPh₃ (221.2 g, 843.23 mmol, 2.6 equiv) in portions at 0° C.under nitrogen atmosphere. The resulting mixture was stirred overnightat room temperature. The residue was purified by silica gel columnchromatography with PE/EtOAc (50/1) as eluent to afford the titlecompound (73 g, 78.06%) as a yellow oil. LC-MS: (ES, m/z): [M+H]⁺ 289.

Step 2: Synthesis of1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylic acid

To a stirred solution of ethyl1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylate (36.7 g,127.28 mmol, 1 equiv) in EtOH (367 mL) was added NaOH (4M) (63.64 mL, 2equiv). The resulting mixture was stirred for 1 h at 40° C. and thenquenched with water at room temperature. The reaction mixture wasacidified to pH 4 with HCl (2M) (aq.) and the resulting mixture wasextracted with EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure to give the title compound (30 g, 90.55%) as a whitesolid. LC-MS: (ES, m/z): [M+H]⁺ 261.

Step 3: Synthesis of1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carbonyl chloride

To a stirred solution of1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carboxylic acid (15 g,57.63 mmol, 1 equiv) and DMF (0.4 g, 5.76 mmol, 0.1 equiv) in DCM (300mL) was added (COCl)₂ (11.0 g, 86.44 mmol, 1.5 equiv) dropwise at 0° C.The resulting mixture was stirred for 3 h at room temperature and thenconcentrated under reduced pressure to give the title compound (17 g,crude) as a white solid.

Step 4: Synthesis of1-(2-(benzyloxy)ethyl)-N-(2-fluoro-4-bromophenyl)-4-methyl-1H-pyrazole-5-carboxamide

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placed1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-carbonyl chloride (2 g,7.18 mmol, 1 equiv), 4-bromo-2-fluoroaniline (1.6 g, 8.61 mmol, 1.2equiv), Et₃N (1.1 g, 10.76 mmol, 1.5 equiv), and DCM (20 mL). Theresulting solution was stirred for 2 h at 25° C. The reaction was thenquenched with water and the resulting solution was extracted withdichloromethane. The organic layers were concentrated under vacuum. Thecrude product was purified by re-crystallization from CH₃OH to give (2.5g, 80.60%) of the title compound as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 432, 434.

Step 5: Synthesis ofN-(4-bromo-2-fluorophenyl)-1-(2-hydroxyethyl)-4-methyl-1H-pyrazole-5-carboxamide

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placed1-(2-(benzyloxy)ethyl)-N-(2-fluoro-4-bromophenyl)-4-methyl-1H-pyrazole-5-carboxamide(2.5 g, 5.78 mmol, 1 equiv), DCM (25 mL), and BCl₃ (1M) (8.7 mL, 1.5equiv) was added at 0° C. The resulting solution was stirred for 1 h at0° C. The reaction was then quenched with NaHCO₃. The resulting solutionwas extracted with dichloromethane dried over anhydrous sodium sulfateand concentrated under vacuum to give (1.8 g, 94.85%) of the titlecompound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 342, 344.

Step 6: Synthesis of2-(5-((4-bromo-2-fluorophenyl)carbamoyl)-4-methyl-1H-pyrazol-1-yl)ethylmethanesulfonate

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplacedN-(4-bromo-2-fluorophenyl)-1-(2-hydroxyethyl)-4-methyl-1H-pyrazole-5-carboxamide(1.8 g, 5.26 mmol, 1 equiv), Et₃N (0.8 g, 7.89 mmol, 1.5 equiv), and DCM(40 mL), and MsCl (0.9 g, 7.89 mmol, 1.5 equiv) was added at 0° C. Theresulting solution was stirred for 1 h at 0° C. The reaction mixture wasthen quenched with water and the resulting solution was extracted withdichloromethane dried over anhydrous sodium sulfate and concentrated togive (2.2 g, 99.51%) the title compound as a white solid. LC-MS: (ES,m/z): [M+H]⁺ 420, 422.

Step 7: Synthesis of5-(4-bromo-2-fluorophenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced2-(5-((4-bromo-2-fluorophenyl)carbamoyl)-4-methyl-1H-pyrazol-1-yl)ethylmethanesulfonate (2.2 g, 5.23 mmol, 1 equiv), DMF (45 mL), and NaH (0.33g, 13.75 mmol, 2.63 equiv) was added at 0° C. The resulting solution wasstirred for 1 h at 0° C. The reaction was then quenched with NH₄Cl, theresulting solution was extracted with ethyl acetate and the organiclayer concentrated. The residue was applied onto a silica gel column andeluted with dichloromethane/methanol (50/1) to give (1.65 g, 97.23%) ofthe title compound as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 324, 326.

Step 8: Synthesis of5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placed5-(4-bromo-2-fluorophenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (1.65 g, 5.09 mmol, 1 equiv), B2Pin2 (1.9 g, 7.64 mmol, 1.5equiv), KOAc (1.0 g, 10.18 mmol, 2 equiv), dioxane (20 mL), andPd(dppf)Cl₂ (0.6 g, 0.76 mmol, 0.15 equiv). The resulting solution wasstirred for 12 h at 80° C. The resulting mixture was concentrated andthe residue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1/10) to give (1.85 g, 97.91%) the titlecompound as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 372.

Step 9: Synthesis of5-(2-fluoro-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placed5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (1 g, 2.69 mmol, 1 equiv),2-chloro-6-(trifluoromethyl)quinazoline (0.8 g, 3.23 mmol, 1.2 equiv),K₂CO₃ (1.1 g, 8.08 mmol, 3 equiv), toluene (16 mL), EtOH (8 mL), andPd(PPh₃)₄ (0.5 g, 0.40 mmol, 0.15 equiv). The resulting solution wasstirred for 12 h at 80° C. The reaction was then quenched with water andthe resulting solution was extracted with ethyl acetate. The organicswere concentrated and the residue was applied onto a silica gel columnand eluted with ethyl acetate/petroleum ether (1/5) to give (554.4 mg,(46.63%) of the title compound as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 442. ¹H-NMR: (300 MHz, DMSO, ppm): δ 2.27 (s, 3H), 4.21-4.25 (dd,2H), 4.51-4.55 (dd, 2H), 7.51 (s, 1H), 7.75 (t, 1H), 8.27-8.34 (m, 2H),8.38-8.43 (dd, 1H), 8.49-8.52 (dd, 1H), 8.75 (s, 1H), 9.92 (s, 1H).

Example 14 Synthesis of1-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one

Step 1: Synthesis of methyl 1-methyl-4-vinyl-1H-pyrazole-5-carboxylate

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placedmethyl 4-bromo-1-methyl-1H-pyrazole-5-carboxylate (1 g, 4.57 mmol, 1equiv), tributyl(ethenyl)stannane (1.4 g, 4.41 mmol, 0.97 equiv),Pd(PPh₃)₄ (0.5 g, 0.43 mmol, 0.09 equiv) in DMF (10 mL). The resultingsolution was stirred overnight at 100° C. The resulting solution wasdiluted with H₂O and extracted with ethyl acetate and the organic layerconcentrated. The residue was applied onto a silica gel column andeluted with EA/PE (1:1) to give the title compound (580 mg 76.45%) ascolorless oil. LC-MS: (ES, m/z): [M+H]⁺ 167.

Step 2: Synthesis of 1-methyl-4-vinyl-1H-pyrazole-5-carboxylic acid

Into a 25-mL round-bottom flask, was placed methyl1-methyl-4-vinyl-1H-pyrazole-5-carboxylate (560 mg, 3.37 mmol, 1 equiv),LiOH (96.8 mg, 4.04 mmol, 1.20 equiv), THF (5 mL, 61.71 mmol, 18.31equiv), and H₂O (5 mL, 277.54 mmol, 82.36 equiv). The resulting solutionwas stirred overnight at room temperature and then diluted with H₂O. Theresulting mixture was concentrated, extracted with ethyl acetate, driedover anhydrous sodium sulfate and concentrated to give (380 mg, 74.11%)the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 153.

Step 3: Synthesis of 1-methyl-4-vinyl-1H-pyrazole-5-carbonyl chloride

Into a 100 mL 3-necked round-bottom flask were added1-methyl-4-vinyl-1H-pyrazole-5-carboxylic acid (1.92 g, 12.62 mmol, 1equiv), DCM (40 mL), DMF (0.1 g, 1.26 mmol, 0.1 equiv) and (COCl)₂ (2.4g, 18.91 mmol, 1.50 equiv) was added at 0° C. The resulting mixture wasstirred for 2 h at room temperature and then concentrated under reducedpressure to afford the title compound (2.3 g, 106.84%) as a yellowsolid. The crude product was used in the next step directly withoutfurther purification.

Step 4: Synthesis ofN-(4-bromo-2-methylphenyl)-1-methyl-4-vinyl-1H-pyrazole-5-carboxamide

Into a 100 mL 3-necked round-bottom flask were added4-bromo-2-methylaniline (2.4 g, 12.97 mmol, 1.02 equiv), DCM (40 mL),Et₃N (1.9 g, 18.78 mmol, 1.48 equiv) and4-ethenyl-1-methyl-1H-pyrazole-5-carbonyl chloride (2.16 g, 12.66 mmol,1 equiv) at 0° C. The resulting mixture was stirred for 2 h at roomtemperature and then diluted with water. The aqueous layer was extractedwith CH₂Cl₂ and the organics were separated and concentrated undervacuum. The crude product was recrystallized from MeOH (20 mL) to givethe title compound (3.8 g, 93.73%) as a light yellow solid. LC-MS: (ES,m/z): [M+H]⁺ 320, 322.

Step 5: Synthesis ofN-(4-bromo-2-methylphenyl)-4-(1,2-dihydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 8 mL sealed tube were addedN-(4-bromo-2-methylphenyl)-1-methyl-4-vinyl-1H-pyrazole-5-carboxamide(200 mg, 0.62 mmol, 1 equiv), NMO (219.5 mg, 1.87 mmol, 3.00 equiv), THF(2 mL), H₂O (0.2 mL) and OsO₄ (7.9 mg, 0.03 mmol, 0.05 equiv). Theresulting mixture was stirred for 4 h at room temperature under nitrogenatmosphere. The reaction was quenched with Na₂S₂O₄ (aq.) at roomtemperature. The aqueous layer was extracted with EtOAc and theresulting mixture was concentrated under reduced pressure to afford thetitle compound (208 mg, 94.01%) as a yellow solid. LC-MS: (ES, m/z):[M+H]⁺ 354, 356.

Step 6: Synthesis ofN-(4-bromo-2-methylphenyl)-4-formyl-1-methyl-1H-pyrazole-5-carboxamide

Into a 8 mL sealed tube were addedN-(4-bromo-2-methylphenyl)-4-(1,2-dihydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide(208 mg, 0.59 mmol, 1 equiv), MeOH (2 mL), H₂O (0.2 mL) and NaIO₄ (251.2mg, 1.17 mmol, 2.00 equiv). The resulting mixture was stirred for 4 h atroom temperature and then diluted with water. The aqueous layer wasextracted with EtOAc and the resulting mixture was concentrated undervacuum to afford the title compound (180 mg, 95.15%) as a yellow solid.LC-MS: (ES, m/z): [M+H]⁺ 322, 324.

Step 7: Synthesis ofN-(4-bromo-2-methylphenyl)-4-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxamide

Into a 8 mL sealed tube were addedN-(4-bromo-2-methylphenyl)-4-formyl-1-methyl-1H-pyrazole-5-carboxamide(180 mg, 0.56 mmol, 1 equiv), MeOH (1.8 mL) and NaBH₄ (25.4 mg, 0.67mmol, 1.20 equiv) was added at 0° C. The resulting mixture was stirredfor 4 h at room temperature under nitrogen atmosphere. The reaction wasquenched with sat. NH₄Cl (aq.). The resulting mixture was concentratedunder vacuum and the aqueous layer was extracted with EtOAc. The organiclayer was concentrated under vacuum to the title compound (161 mg,88.89%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 324, 326.

Step 8: Synthesis of(5-((4-bromo-2-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)methylmethanesulfonate

Into a 8 mL sealed tube were addedN-(4-bromo-2-methylphenyl)-4-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxamide(161 mg, 0.50 mmol, 1 equiv), DCM (3.22 mL), and Et₃N (75.4 mg, 0.74mmol, 1.50 equiv) and MsCl (87.6 mg, 0.76 mmol, 1.54 equiv) was added at0° C. The resulting mixture was stirred for 2 h at room temperature andthen diluted with water. The aqueous layer was extracted with CH₂Cl₂ andthe organics were concentrated under reduced pressure to afford thetitle compound (230 mg, 115.13%) as a yellow solid. The crude productwas used in the next step directly without further purification.

Step 9: Synthesis of5-(4-bromo-2-methylphenyl)-1-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one

Into a 25 mL 3-necked round-bottom flask were added(5-((4-bromo-2-methylphenyl)carbamoyl)-1-methyl-1H-pyrazol-4-yl)methylmethanesulfonate (220 mg, 0.55 mmol, 1 equiv), and DMF (4.4 mL) and NaH(19.7 mg, 0.82 mmol, 1.50 equiv) was added at 0° C. in portions. Theresulting mixture was stirred for 2 h at room temperature under nitrogenatmosphere. The reaction was quenched with sat. NH₄Cl (aq.). The aqueouslayer was extracted with EtOAc and the organics were concentrated underreduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 2:1) toafford the title compound (110 mg, 65.69%) as a yellow solid. LC-MS:(ES, m/z): [M+H]⁺ 306, 308

Step 10: Synthesis of1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one

Into a 8 mL sealed tube were added5-(4-bromo-2-methylphenyl)-1-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (110 mg, 0.36 mmol, 1 equiv),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(100.4 mg, 0.40 mmol, 1.10 equiv), KOAc (70.5 mg, 0.72 mmol, 2 equiv),dioxane (2.2 mL) and Pd(dppf)Cl₂ (26.3 mg, 0.04 mmol, 0.1 equiv). Thereaction mixture was stirred overnight at 80° C. under nitrogenatmosphere and concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluting with PE/EtOAc(1:1) to afford the title compound (120 mg, 94.55%) as a yellow solid.LC-MS: (ES, m/z): [M+H]⁺ 354.

Step 11: Synthesis of1-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one

Into a 8 mL sealed tube were added1-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (110 mg, 0.31 mmol, 1 equiv),2-chloro-6-(trifluoromethyl)quinazoline (72.4 mg, 0.31 mmol, 1.00equiv), K₂CO₃ (129.1 mg, 0.93 mmol, 3 equiv), toluene (2.2 mL), EtOH(1.1 mL) and Pd(PPh₃)₄ (36.0 mg, 0.03 mmol, 0.1 equiv). The resultingmixture was stirred overnight at 80° C. under nitrogen atmosphere, thenconcentrated under reduced pressure. The residue was purified byPrep-TLC (PE/EtOAc 1:1) to afford the title compound (57.8 mg, 43.84%)as a light yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 424; ¹H-NMR: (300 MHz,DMSO-d₆, ppm): δ 2.35 (s, 3H), 4.01 (s, 3H), 4.73 (s, 2H), 7.59 (s, 1H),7.62 (d, 1H), 8.28 (m, 2H), 8.49 (dd, 1H), 8.57 (s, 1H), 8.73 (s, 1H),9.91 (s, 1H).

Example 15 Synthesis of1-methyl-6-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, was placed1-methyl-6-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one(1 g, 2.72 mmol, 1 equiv), 2-chloro-6-(trifluoromethyl)quinazoline(633.3 mg, 2.72 mmol, 1 equiv), K₂CO₃ (1128.9 mg, 8.17 mmol, 3.00equiv), toluene (10 mL), EtOH (5 mL), and Pd(PPh₃)₄ (314.6 mg, 0.27mmol, 0.1 equiv). The resulting solution was stirred overnight at 80°C., diluted with EtOAc and washed with H₂O. The organic layer wasconcentrated and the residue was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (1:2) to give (516.6 mg,43.37%) of the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺438; ¹H-NMR: (400 MHz, DMSO-d6, ppm): δ 9.90 (s, 1H), 8.72 (s, 1H),8.54-8.55 (d, 1H), 8.47-8.49 (m, 1H), 8.25-8.30 (m, 2H), 7.48-7.53 (m,2H), 4.05-4.12 (m, 4H), 3.72-3.78 (m, 1H), 2.91-3.05 (m, 2H), 2.34 (s,3H).

Example 16 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution of 2-chloro-6-(trifluoromethyl)quinazoline (1.5 g,6.42 mmol, 1 equiv) and3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2.4 g, 6.42 mmol, 1 equiv) in t-BuOH (27 mL) and H₂O (3 mL)were added K₂CO₃ (2.7 g, 19.27 mmol, 3 equiv) and AMPhosPdCl₂ (1.4 g,1.93 mmol, 0.3 equiv). The resulting mixture was stirred overnight at80° C. under nitrogen atmosphere and then diluted with water. Theresulting mixture was extracted with EtOAc and the combined organiclayers were concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, by eluting with PE/EtOAc(1/2) to give crude product. The residue was purified by reverse flashchromatography with the following conditions: column, C18 gel; mobilephase, ACN and water (10 mmol/LNH₄HCO₃), 0% to 65% gradient in 40 min;detector, UV 254 nm to give the title compound (535.6 mg, 19.02%) as ayellow solid. LC-MS: (ES, m/z): [M+H]⁺ 439; ¹H-NMR: (300 MHz, DMSO-d₆,ppm): δ 2.26 (s, 3H), 2.36 (s, 3H), 3.91-3.95 (m, 1H), 4.28-4.36 (m,1H), 4.51-4.55 (t, 2H), 7.48 (s, 1H), 7.57-7.60 (d, 1H), 8.46-8.57 (m,3H), 8.81-8.84 (d, 1H), 9.97 (s, 1H).

Example 17 Synthesis of3-methyl-5-(2-methyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution of6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridine (500 mg, 2.03mmol, 1 equiv) and3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (744.6 mg, 2.03 mmol, 1.00 equiv) in DME (10 mL) and H₂O (2.5mL) were added Na₂CO₃ (429.8 mg, 4.05 mmol, 2 equiv) and Pd(PPh₃)₄(234.3 mg, 0.20 mmol, 0.1 equiv) at room temperature under nitrogenatmosphere. The resulting mixture was stirred overnight at 80° C. undernitrogen atmosphere. The reaction mixture was diluted with water at roomtemperature and extracted with EtOAc. The organic layer was concentratedunder vacuum and the residue was purified by silica gel columnchromatography by eluting with PE/EtOAc (1:2) to afford crude product.The crude product was re-crystallized from MeOH (10 mL) to afford thetitle compound (652 mg, 71.23%) as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 452; 1H-NMR: (300 MHz, DMSO-d₆, ppm): δ 2.26 (s, 3H), 2.35 (s,3H), 2.97 (s, 3H), 3.94-3.98 (m, 1H), 4.28-4.37 (m, 1H), 4.53 (t, 2H),7.47 (s, 1H), 7.56 (d, 1H), 8.16 (s, 1H), 8.26-8.33 (m, 2H), 8.62 (q,2H).

Example 18 Synthesis of5-(2,5-dimethyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding as described in Example 5, Step 12 above, but substituting6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridine with2-chloro-6-(trifluoromethyl)-1,5-naphthyridine and7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with5-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one gave crude product. Purification by silica gel columnchromatography using ethyl acetate/petroleum ether (1/1) as eluent gavethe title compound as a white solid in 51.79% yield. LC-MS: (ES, m/z):[M+H]⁺ 452; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 2.19 (s, 6H), 2.40 (s,3H), 3.89-3.94 (m, 1H), 4.22-4.31 (m, 1H), 4.50-4.54 (t, 2H), 7.38 (s,1H), 7.48 (s, 1H), 7.56 (s, 1H), 8.18 (d, 1H), 8.28 (d, 1H), 8.69 (d,1H), 8.77 (d, 1H).

Example 19 Synthesis of5-(2,5-dimethyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution of5-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (3.5 g, 9.18 mmol, 1 equiv) and2-chloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine (2.6 g, 11.02 mmol,1.2 equiv) in dioxane (260 mL) were added K₃PO₄ (3.9 g, 18.36 mmol, 2equiv), H₂O (50 mL) and AMPhosPdCl₂ (1.5 g, 2.12 mmol, 0.23 equiv). Theresulting mixture was stirred overnight at 60° C. under nitrogenatmosphere. The resulting mixture was diluted with water and the aqueouslayer was extracted with EtOAc. The combined organic layer wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography, by eluting with PE/EtOAc (3/1). The crudeproduct was re-crystallized from MeOH to afford the title compound(501.0 mg, 12.06%) as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 453;¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 2.26 (s, 3H), 2.28 (s, 3H), 2.62 (s,3H), 3.91-3.95 (m, 1H), 4.24-4.33 (m, 1H), 4.52 (t, 2H), 7.39 (s, 1H),7.48 (s, 1H), 8.01 (s, 1H), 8.49 (d, 1H), 8.82 (d, 1H), 9.98 (s, 1H).

Example 20 Synthesis of5-(2,5-dimethyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding as described in Example 5, Step 12 above, but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with5-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one gave crude product. Purification by silica gel columnchromatography using ethyl acetate/petroleum ether (1:1) as eluent gavethe title compound as a yellow solid in 53.48% yield. LC-MS: (ES, m/z):[M+H]⁺ 466; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 2.26 (s, 6H), 2.46 (s,3H), 2.89 (s, 3H), 3.91-3.95 (m, 1H), 4.23-4.31 (m, 1H), 4.51-4.55 (m,2H), 7.38 (s, 1H), 7.49 (s, 1H), 7.60 (s, 1H), 8.16-8.19 (m, 2H), 8.64(d, 1H).

Example 21 Synthesis of5-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding as described in Example 19 above but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with5-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2 g, 5.19 mmol, 1 equiv) in dioxane (150 mL) gave the titlecompound as a yellow solid after purification by silica gel columnchromatography, using PE/EtOAc (1:1) as an eluent. LC-MS: (ES, m/z):[M+H]⁺ 457; ¹H-NMR: (300 MHz, DMSO, ppm) δ 10.00 (s, 1H), 8.85 (d, 1H),8.52 (d, 1H), 7.97 (d, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 4.52 (t, 2H),4.21 (t, 2H), 2.66 (s, 3H), 2.26 (s, 3H).

Example 22 Synthesis of5-(2-fluoro-5-methyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding as described in Example 5, Step 12 above, but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with5-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one and 2-chloro-6-trifluoromethyl)-1,5-naphthyridine6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridine gave crudeproduct. Purification by silica gel column chromatography using ethylacetate/petroleum ether (1:5) as eluent gave the title compound as ayellow solid in 59.39% yield. LC-MS: (ES, m/z): [M+H]⁺ 470; ¹H-NMR: (400MHz, DMSO-d₆, ppm): δ 2.27 (s, 3H), 2.49 (s, 3H), 2.91 (s, 3H), 4.19 (t,2H), 4.52 (t, 2H), 7.50 (s, 1H), 7.56 (d, 1H), 7.66 (d, 1H), 8.12-8.23(m, 2H), 8.67 (d, 1H).

Example 23 Synthesis of5-(2,5-dimethyl-4-(6-(trifluoromethyl)quinolin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding as described in Example 5, Step 12 above, but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with5-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one and 6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridinewith 2-chloro-6-(trifluoromethyl)quinoline gave crude product.Purification by silica gel column chromatography using ethylacetate/petroleum ether (1:1) as eluent, followed by recrystallizationfrom methanol gave the title compound as a yellow solid in 63.90% yield.LC-MS: (ES, m/z): [M+H]⁺ 451; ¹H-NMR: (300 MHz, DMSO, ppm): δ 2.25 (s,3H), 2.26 (s, 3H), 2.38 (s, 3H), 3.89-3.95 (m, 1H), 4.21-4.30 (m, 1H),4.52 (t, 2H), 7.35 (s, 1H), 7.47 (s, 1H), 7.51 (s, 1H), 7.92 (d, 1H),8.05 (dd, 1H), 8.26 (d, 1H), 8.59 (s, 1H), 8.68 (d, 1H).

Example 24 Synthesis of5-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)quinolin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding as described in Example 5, Step 12 above, but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with5-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one and 6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridinewith 2-chloro-6-(trifluoromethyl)quinoline gave crude product.Purification by silica gel column chromatography using ethylacetate/petroleum ether (1:′) as eluent, followed by recrystallizationfrom PE/EtOAc gave the title compound as a white solid in 53.70% yield.LC-MS: (ES, m/z): [M+H]⁺ 455; ¹H-NMR: (400 MHz, DMSO-d6, ppm): δ 2.27(s, 3H), 2.41 (s, 3H), 4.18 (t, 2H), 4.52 (t, 2H), 7.49-7.57 (m, 3H),7.95 (d, 1H), 8.06 (dd, 1H), 8.26 (d, 1H), 8.60 (s, 1H), 8.71 (d, 1H).

Example 25 Synthesis of5-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding as described in Example 2, Step 11 above, but substituting3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one with5-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one gave the title compound. Recrystallization from methanol gavepure product as a white solid in 56.68% yield. LC-MS: (ES, m/z): [M+H]⁺456; ¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 2.27 (s, 3H), 2.73 (s, 3H), 4.20(t, 2H), 4.52 (t, 2H), 7.50 (s, 1H), 7.55 (d, 1H), 7.94 (d, 1H),8.27-8.35 (m, 2H), 8.78 (s, 1H), 9.94 (s, 1H).

Example 26 Synthesis of5-(2-fluoro-5-methyl-4-(8-methyl-6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding as described in Example 2, Step 11 above but substituting3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one with5-(2-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one and 2-chloro-6-(trifluoromethyl)-quinazoline with2-chloro-8-methyl-6-(trifluoromethyl)-quinazoline gave the titlecompound as a white solid in 71.50% yield. LC-MS: (ES, m/z): [M+H]⁺ 470;¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 2.27 (s, 3H), 2.71 (s, 3H), 2.82 (s,3H), 4.20 (t, 2H), 4.52 (t, 2H), 7.49 (s, 1H), 7.56 (d, 1H), 8.05 (d,1H), 8.20 (s 1H), 8.56 (s, 1H), 9.88 (s, 1H).

Example 27 Synthesis of1-methyl-6-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Proceeding as described in Example 5, Step 12 above, but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with1-methyl-6-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-oneand 6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridine with2-chloro-6-(trifluoromethyl)-1,5-naphthyridine gave crude product.Purification by silica gel column chromatography using ethylacetate/petroleum ether (1:5) as eluent gave the title compound as awhite solid in 49% yield. LC-MS: (ES, m/z): [M+H]⁺ 438; ¹H-NMR: (400MHz, DMSO, ppm): δ 2.34 (s, 3H), 2.91-3.05 (m, 2H), 3.72-3.77 (m, 1H),4.05-4.12 (m, 4H), 7.49-7.54 (m, 2H), 8.24-8.26 (d, 2H), 8.33 (s, 1H),8.60-8.62 (d, 1H), 8.68-8.80 (d, 1H), 8.79-8.80 (d, 1H).

Example 28 Synthesis of1-methyl-6-(2-methyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one

Proceeding as described in Example 5, Step 12 above, but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with1-methyl-6-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-onegave crude product. Purification by silica gel column chromatographyusing ethyl acetate/petroleum ether (1:2) as eluent gave the titlecompound as a white solid in 72.20% yield. LC-MS: (ES, m/z): [M+H]⁺ 452;¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 8.64 (d, 1H), 8.58 (d, 1H), 8.32 (s,1H), 8.26 (dd, 1H), 8.15 (s, 1H), 7.52 (d, 1H), 7.48 (s, 1H), 4.05-4.12(m, 4H), 3.72-3.78 (m, 1H), 2.90-3.03 (m, 5H), 2.34 (s, 3H).

Example 29 Synthesis of1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 2, Step 11 above but substituting3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one with1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provide crude product. Purification of the crude product bysilica gel column chromatography, by eluting with PE/EtOAc (3/1),followed by re-crystallized from PE/EtOAc (10/1, 50 mL) provided thetitle compound as an off-white solid in 48.59% yield. LC-MS: (ES, m/z):[M+H]⁺ 454; 1H-NMR: (300 MHz, DMSO, ppm): δ 2.34 (s, 3H), 3.97-4.05 (m,5H), 4.46-4.58 (m, 2H), 7.37 (s, 1H), 7.48 (d, 1H), 8.25 (m, 2H), 8.48(dd, 1H), 8.55 (d, 1H), 8.73 (s, 1H), 9.90 (s, 1H).

Example 30 Synthesis of1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 5, Step 12 above, but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one and 6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridinewith 2-chloro-6-(trifluoromethyl)-1,5-naphthyridine gave crude product.Purification by silica gel column chromatography using ethylacetate/petroleum ether (1:3) as eluent, followed by recrystallizationfrom PE/EtOAc (10:1) gave the title compound as an off-white solid in69.10% yield. LC-MS: (ES, m/z): [M+H]⁺ 454; ¹H-NMR: (300 MHz, DMSO-d₆,ppm): δ 2.34 (s, 3H), 3.99-4.04 (m, 5H), 4.46-4.59 (m, 2H), 7.37 (s,1H), 7.48 (d, 1H), 8.22-8.26 (m, 2H), 8.32 (d, 1H), 8.61 (d, 1H), 8.70(d, 1H), 8.79 (d, 1H).

Example 31 Synthesis of1-methyl-7-(2-methyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 5, Step 12 above, but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one gave crude product. Purification by silica gel columnchromatography using ethyl acetate/petroleum ether (1:3) as eluent,followed by recrystallization from PE/EtOAc (10:1) gave the titlecompound as an off-white solid in 82% yield. LC-MS: (ES, m/z): [M+H]⁺468; ¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 2.34 (s, 3H), 2.96 (s, 3H),3.99-4.05 (m, 5H), 4.46-4.59 (m, 2H), 7.37 (s, 1H), 7.48 (d, 1H), 8.15(d, 2H), 8.25 (dd, 1H), 8.31 (d, 1H), 8.57 (d, 1H), 8.64 (d, 1H).

Example 32 Synthesis of7-(2,5-dimethyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 5, Step 12 above, but substituting6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridine with6-chloro-2-(trifluoromethyl)-1,5-naphthyridine gave crude product.Purification by silica gel column chromatography using ethylacetate/petroleum ether (1:10) as eluent gave the title compound as awhite solid in 77.20% yield. LC-MS: (ES, m/z): [M+H]⁺ 468; ¹H-NMR: (300MHz, DMSO, ppm): δ 2.24 (s, 3H), 2.40 (s, 3H), 3.97-4.01 (m, 5H),4.46-4.58 (m, 2H), 7.29 (s, 1H), 7.36 (s, 1H), 7.54 (s, 1H), 8.16 (d,1H), 8.27 (d, 1H), 8.69 (d, 1H), 8.77 (d, 1H).

Example 33 Synthesis of7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of methyl4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate

Into a 250-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced methyl 4-bromo-1H-pyrazole-5-carboxylate (7 g, 34.14 mmol, 1equiv), 3,4-dihydro-2H-pyran (5.7 g, 68.29 mmol, 2 equiv), EA (70 mL),and PTSA (0.9 g, 5.12 mmol, 0.15 equiv). The resulting solution wasstirred for 12 h at 80° C. and then quenched with water. The resultingsolution was extracted with ethyl acetate. The residue was applied ontoa silica gel column and eluted with ethyl acetate/petroleum ether (1:20)to give (7.1 g, 71.92%) of the title compound as a yellow liquid. LC-MS:(ES, m/z): [M+H]⁺ 289

Step 2: Synthesis of4-(2-(benzyloxy)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylicacid

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced methyl4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate (7 g,24.21 mmol, 1 equiv), 2-(benzyloxy)ethan-1-ol (25 mL), Cs₂CO₃ (23.7 g,72.63 mmol, 3 equiv), CuCl₂ (0.3 g, 2.42 mmol, 0.1 equiv). The resultingsolution was stirred for 12 h at 130° C. The resulting solution wasextracted with ethyl acetate and the pH value of the solution wasadjusted to 5 with HOAc. The resulting solution was extracted with ethylacetate and the organic layer was concentrated. The residue was appliedonto a silica gel column and eluted with ethyl acetate/petroleum ether(1:1) to give (3.1 g, 36.97%) of the title compound as a yellow liquid.LC-MS: (ES, m/z): [M+H]⁺ 347.

Step 3: Synthesis of4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced4-(2-(benzyloxy)ethoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylicacid (3.07 g, 8.86 mmol, 1 equiv), 4-bromo-2-methylaniline (2.0 g, 10.64mmol, 1.2 equiv), DIEA (2.3 g, 17.73 mmol, 2 equiv), DMF (30 mL), andHATU (5.1 g, 13.29 mmol, 1.5 equiv). The resulting solution was stirredfor 12 h at 25° C. and then quenched with water. The resulting solutionwas extracted with ethyl acetate. The residue was applied onto a silicagel column and eluted with ethyl acetate/petroleum ether (1:5). Thecrude product was purified by re-crystallization from MeOH to give (2.88g, 63.17%) of the title compound as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 514.

Step 4: Synthesis of4-(2-(benzyloxy)ethoxy)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide(2.88 g, 5.60 mmol, 1 equiv), B₂Pin₂ (2.1 g, 8.27 mmol, 1.48 equiv),KOAc (1.1 g, 11.20 mmol, 2 equiv), dioxane (30 mL), and Pd(dppf)Cl₂ (0.6g, 0.84 mmol, 0.15 equiv). The resulting solution was stirred for 12 hat 80° C. and the resulting mixture was concentrated. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/petroleumether (1:5) to give (2.5 g, 81.57%) of the title compound as a yellowsolid. LC-MS: (ES, m/z): [M+H]⁺ 562.

Step 5: Synthesis of4-(2-hydroxyethoxy)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide

Into a 250-mL 3-necked round-bottom flask, was placed4-(2-(benzyloxy)ethoxy)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide(2.46 g, 4.49 mmol, 1 equiv), MeOH (100 mL), and Pd/C (0.5 g), H_(2(g))passed through the reaction mixture. The resulting solution was stirredfor 2 h at 70° C. under the atmosphere of H₂. The solids were filteredout and the filtrate was concentrated to give (1.7 g, 80.26%) of thetitle compound as a white solid. LC-0575-5: (ES, m/z): [M+H]⁺ 472.

Step 6: Synthesis of2-((5-((2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)ethylmethanesulfonate

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced4-(2-hydroxyethoxy)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide(1.68 g, 3.56 mmol, 1 equiv), Et₃N (0.7 g, 7.13 mmol, 2 equiv), and DCM(40 mL), and MsCl (0.8 g, 7.13 mmol, 2 equiv) was added dropwise. Theresulting solution was stirred for 1 h at 0° C. and then quenched withwater. The resulting solution was extracted with dichloromethane and theorganic layer was concentrated. The crude product was purified byre-crystallization from MeOH to give (1.85 g, 94.47%) of the titlecompound as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 550.

Step 7: Synthesis of7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced2-((5-((2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)ethylmethanesulfonate (1.84 g, 3.35 mmol, 1 equiv) and DMF (40 mL), and NaH(60%) (0.27 g, 11.25 mmol, 3.36 equiv) was added at 0° C. The resultingsolution was stirred for 1 h at 0° C. and then quenched with NH₄Cl(aq.).The resulting solution was extracted with ethyl acetate and the organiclayer was concentrated. The residue was applied onto a silica gel columnand eluted with dichloromethane/methanol (50:1) to give (1.45 g, 95.51%)of the title compound as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺=454.

Step 8: Synthesis of7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-Yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wasplaced7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (1.42 g, 3.13 mmol, 1 equiv),2-chloro-6-(trifluoromethyl)quinazoline (0.9 g, 3.76 mmol, 1.2 equiv),K₂CO₃ (1.3 g, 9.40 mmol, 3 equiv), toluene (20 mL), EtOH (10 mL), andPd(PPh₃)₄ (0.5 g, 0.47 mmol, 0.15 equiv). The resulting solution wasstirred for 12 h at 80° C. and then concentrated under vacuum. Theresidue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:1). The crude product was purified byre-crystallization from MeOH to give (1.4 g, 85.38%) of the titlecompound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 524.

Step 9: Synthesis of7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, was placed7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (1.4 g, 2.67 mmol, 1 equiv) in HCl/dioxane (10 mL). Theresulting solution was stirred for 1 h at 25° C. and then quenched bythe addition of 20 mL of NaHCO₃(aq.). The resulting solution wasextracted with dichloromethane. The residue was applied onto a silicagel column and eluted with ethyl acetate/petroleum ether (1:1) to give(0.8 g, 68.08%) of the title compound as a white solid. LC-MS: (ES,m/z): [M+H]⁺ 440. ¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 2.27 (s, 3H),3.93-4.09 (m, 2H), 4.41-4.61 (m, 2H), 7.40 (s, 1H), 7.48 (d, 1H), 8.28(t, 2H), 8.47 (dd, 2H), 8.54 (s, 1H), 8.73 (s, 1H), 9.90 (s, 1H),13.13-13.20 (s, 1H).

Example 34 Synthesis1-(2-hydroxyethyl)-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of1-(2-(benzyloxy)ethyl)-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 8-mL sealed tube under N₂ atmosphere, was placed7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (200 mg, 0.46 mmol, 1 equiv), [(2-bromoethoxy)methyl]benzene(107.7 mg, 0.50 mmol, 1.1 equiv), and K₂CO₃ (125.8 mg, 0.91 mmol, 2equiv) in DMF (2 mL). The resulting solution was stirred for 12 h at 80°C. and then quenched with water. The resulting solution was extractedwith ethyl acetate and the organic layer was concentrated. The residuewas applied onto Prep-TLC and eluted with ethyl acetate/petroleum ether(1:1) to give (100 mg, 38.30%) of the title compound as a yellow solid.LC-MS-PH: (ES, m/z): [M+H]⁺ 574.

Step 2: Synthesis1-(2-hydroxyethyl)-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 8-mL sealed tube under N₂ atmosphere, was placed1-(2-(benzyloxy)ethyl)-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (100 mg, 0.17 mmol, 1 equiv), DCM (2 mL), and BCl₃ (0.26 mL,0.26 mmol, 1.5 equiv). The resulting solution was stirred for 1 hr at 0°C. The reaction was then quenched with 20 mL of NaHCO₃ and the resultingsolution was extracted with ethyl acetate. The residue was applied ontoPrep-TLC and eluted with dichloromethane/methanol (20:1) to give (48.2mg, 57.19%) of the title compound as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 484. ¹H-NMR-PH-IDE-0578-0: (300 MHz, DMSO-d6, ppm): δ 2.33 (s,3H), 3.62-3.68 (m, 2H), 3.64 (q, 2H), 4.37-4.44 (m, 1H), 4.46-4.63 (m,3H), 4.75-4.78 (m, 1H), 7.39 (s, 1H), 7.47 (d, 1H), 8.25 (s, 1H), 8.30(d, 1H), 8.50 (s, 1H), 8.73 (s, 1H), 9.91 (s, 1H).

Example 35 Synthesis of2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-2H-pyrazolo[3,4-f][1,4]oxazepin-2-yl)acetonitrile

To a stirred mixture of7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (240 mg, 0.55 mmol, 1 equiv) and 2-bromoacetonitrile (131.0 mg,1.09 mmol, 2 equiv) in DMF (4.8 mL) were added K₂CO₃ (226.5 mg, 1.64mmol, 3 equiv). The resulting mixture was stirred for overnight at 80°C. in an oil bath. The reaction was quenched with water and extractedwith EtOAc. The combined organic layers were concentrated under reducedpressure. The residue was purified by Prep-TLC (CH₂Cl₂/MeOH 30/1) toafford the title compound (50 mg, 19.13%) as a grey solid. LC-MS: (ES,m/z): [M+H]⁺ 479. ¹H-NMR: (400 MHz, DMSO-d6, ppm): δ 2.32 (s, 3H),3.95-4.06 (m, 2H), 4.44-4.58 (m, 2H), 5.54 (s, 2H), 7.46 (d, 1H), 7.82(s, 1H), 8.28 (s, 2H), 8.48 (d, 1H), 8.54 (s, 1H), 8.73 (s, 1H), 9.91(s, 1H).

Example 36 Synthesis of2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepin-1-yl)acetonitrile

To a stirred mixture of7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (240 mg, 0.55 mmol, 1 equiv) and 2-bromoacetonitrile (131.0 mg,1.09 mmol, 2 equiv) in DMF (4.8 mL) was added K₂CO₃ (226.5 mg, 1.64mmol, 3 equiv). The resulting mixture was stirred overnight at 80° C. inan oil bath. The reaction was quenched with water and the resultingmixture was extracted with EtOAc. The combined organic layers wereconcentrated under reduced pressure. The residue was purified byPrep-TLC (CH₂Cl₂/MeOH 30/1) to afford the title compound (80 mg, 30.61%)as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 479. ¹H-NMR: (300 MHz,DMSO-d6, ppm): δ 2.35 (s, 3H), 4.04-4.10 (m, 2H), 4.53-4.65 (m, 2H),5.55-5.68 (m, 2H), 7.50 (d, 1H), 7.63 (s, 1H), 8.28 (s, 2H), 8.49 (dd,1H), 8.55 (s, 1H), 8.73 (s, 1H), 9.91 (s, 1H).

Example 37 Synthesis of2-(2-hydroxyethyl)-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of2-(2-(benzyloxy)ethyl)-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 8-mL sealed tube under N₂ atmosphere, was placed7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (200 mg, 0.46 mmol, 1 equiv), [(2-bromoethoxy)-methyl]benzene(107.7 mg, 0.50 mmol, 1.1 equiv), and K₂CO₃ (125.8 mg, 0.91 mmol, 2equiv) in DMF (2 mL). The resulting solution was stirred for 12 h at 80°C. The reaction was then quenched with water. The resulting solution wasextracted with ethyl acetate and the organic layer concentrated. Theresidue was applied onto Prep-TLC and eluted with ethylacetate/petroleum ether (1:1) to give (100 mg, 38.30%) of the titlecompound as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 574.

Step 2: Synthesis of2-(2-hydroxyethyl)-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 8-mL sealed tube under N₂ atmosphere, was placed2-(2-(benzyloxy)ethyl)-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (100 mg, 0.17 mmol, 1 equiv) in DCM (2 mL) and BCl₃ (30.3 mg,0.26 mmol, 1.5 equiv) was added. The resulting solution was stirred for1 h at 0° C. The reaction mixture was then quenched with NaHCO₃ and theresulting solution was extracted with ethyl acetate. The residue wasapplied onto Prep-TLC and eluted with dichloromethane/methanol (20:1) togive (19.7 mg, 23.37%) of the title compound as a yellow solid. LC-MS:(ES, m/z): [M+H]⁺ 484. ¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 2.35 (s, 3H),3.66-3.78 (m, 2H), 3.76-3.97 (m, 2H), 4.15-4.25 (m, 2H), 4.43-4.68 (m,2H), 4.88-5.10 (m, 1H), 7.43 (d, 1H), 7.65 (s, 1H), 8.27 (s, 2H), 8.48(d, 1H), 8.52 (s, 1H), 8.82 (s, 1H), 9.98 (s, 1H).

Example 38 Synthesis of7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 2, Step 11, butsubstituting3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one with7-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(oxan-2-yl)-1H,5H,6H,7H,8H-pyrazolo[3,4-f][1,4]oxazepin-8-oneand 2-chloro-6-(trifluoromethyl)-quinazoline with2-chloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine gave (650 mg,37.45%) of the title compound as a red solid.

Step 2: Synthesis of7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 8-mL vial, was placed7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (600 mg, 1.14 mmol, 1 equiv), dioxane (1 mL), HCl (12M) (1 mL).The resulting solution was stirred for 2 h at room temperature. Thereaction mixture was then quenched by the addition of solution of Na₂CO₃and the resulting solution was extracted with ethyl acetate andconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (30:1). The crude product (70 mg)was purified by Prep-HPLC under the following conditions (2 #SHIMADZU(HPLC-01)): Column, XBridge Prep OBD C18 Column, 30 150 mm 5 um; mobilephase, Water (0.05% NH₃H₂O) and ACN (42% PhaseB up to 52% in 7 min);Detector, UV) to give (13.9 mg, 2.76%) of the title compound as a whitesolid. LC-MS: (ES, m/z): [M+H]⁺ 441.2; ¹H-NMR: (300 MHz, DMSO-d₆, ppm):δ 13.24 (s, 1H) 9.95 (s, 1H), 8.80 (d, 1H), 8.54 (s, 1H), 8.46 (dd, 2H),7.49 (d, 1H), 7.40 (s, 1H), 4.54 (d, 1H), 4.45 (d, 1H), 3.99 (t, 2H),2.32 (s, 3H).

Example 39 Synthesis of7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-3H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of ethyl5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate

Into a 500-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced 1-(azidomethyl)-4-methoxybenzene (20 g, 122.56 mmol, 1 equiv),1,3-diethyl propanedioate (29.4 g, 183.85 mmol, 1.5 equiv), EA (200 mL),and PTSA (3.2 g, 18.38 mmol, 0.15 equiv). The resulting solution wasstirred for 12 h at 80° C. and then concentrated. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/petroleumether (1:20) to give (30 g, 88.28%) of the title compound as a yellowsolid.

Step 2: Synthesis of5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid

Into a 1000-mL 3-necked round-bottom under N₂ atmosphere, were placedethyl 5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylate (30g, 108.19 mmol, 1 equiv), NaOH (4.8 g, 119.01 mmol, 1.1 equiv), H₂O (150mL), and MeOH (300 mL). The resulting solution was stirred for 3 h at25° C. and then concentrated under vacuum. After adding water, the pHvalue of the solution was adjusted to 5 with HCl. The resulting solutionwas extracted with ethyl acetate and concentrated to give (20 g, 74.17%)of the title compound as a yellow solid.

Step 3: Synthesis ofN-(4-bromo-2-methylphenyl)-5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxamide

Into a 500-mL 3-necked round-bottom under N₂ atmosphere, were placed5-hydroxy-1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid (20 g,80.25 mmol, 1 equiv), 4-bromo-2-methylaniline (22.4 g, 120.37 mmol, 1.5equiv), T₃P (38.3 g, 120.37 mmol, 1.5 equiv), DIEA (20.7 g, 160.50 mmol,2 equiv), and THF (200 mL). The resulting solution was stirred for 12 hat 60° C. and then concentrated. The residue was applied onto a silicagel column and eluted with ethyl acetate/petroleum ether (1:20) to give(25 g, 74.66%) of the title compound as a yellow solid.

Step 4: Synthesis of7-(4-bromo-2-methylphenyl)-3-(4-methoxybenzyl)-6,7-dihydro-3H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one

Into a 250-mL 3-necked round-bottom flask under N₂ atmosphere, wereplacedN-(4-bromo-2-methylphenyl)-5-hydroxy-1-(4-methoxy-benzyl)-1H-1,2,3-triazole-4-carboxamide(10 g, 23.97 mmol, 1 equiv), DMF (100 mL), 1,2-dibromoethane (5.4 g,28.76 mmol, 1.2 equiv), and K₂CO₃ (6.6 g, 47.93 mmol, 2 equiv). Theresulting solution was stirred for 12 h at 80° C. and then quenched withwater. The resulting solution was extracted with ethyl acetate and thenconcentrated. The residue was applied onto a silica gel column andeluted with dichloromethane/methanol (30:1) to give (4 g, 37.65%) of thetitle compound as a yellow solid.

Step 5: Synthesis of3-(4-methoxybenzyl)-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-3H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 1, Step 12 butsubstituting7-(4-bromo-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f]-[1,4]oxazepin-8(5H)-one with7-(4-bromo-2-methylphenyl)-3-(4-methoxybenzyl)-6,7-dihydro-3H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one provided (2.6 g, 58.76%) of the title compound as a yellowsolid.

Step 6: Synthesis of3-(4-methoxybenzyl)-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-3H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 5, Step 12, butsubstituting 6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridinewith 2-chloro-6-(trifluoromethyl)-1,5-naphthyridine and7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with3-(4-methoxybenzyl)-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-3H-[1,2,3]triazolo-[4,5-f][1,4]oxazepin-8(5H)-one provided crude product which was purified by re-crystallizationfrom MeOH to give (450 mg, 65.27%) of the title compound as a yellowsolid.

Step 7: Synthesis of7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-3H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one

Into an 8-mL sealed tube under N₂ atmosphere, were placed3-(4-methoxybenzyl)-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-3H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one (400 mg, 0.71 mmol, 1 equiv) and TFA (4 mL). The resultingsolution was stirred for 2 h at 80° C. and then concentrated. The crudeproduct was purified by re-crystallization from MeOH to give (197.9 mg,62.97%) of the title compound as a yellow solid. LC-MS: (ES, m/z):[M+H]⁺ 441.3H; ¹H NMR: (300 MHz, DMSO-d₆, ppm): δ 2.34 (s, 3H),3.88-3.92 (m, 1H), 4.25-4.28 (m, 1H), 4.61-4.67 (m, 2H), 7.52 (d, 1H),8.25 (d, 2H), 8.30 (s, 1H), 8.60 (d, 1H), 8.69 (d, 1H), 8.79 (d, 1H).

Example 40 Synthesis of7-[2-methyl-4-[6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl]phenyl]-1H,5H,6H,7H,8H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8-one

Step 1: Synthesis of1-[(4-methoxyphenyl)methyl]-7-[2-methyl-4-[6-(trifluoromethyl)-pyrido-[3,2-d]pyrimidin-2-yl]phenyl]-1H,5H,6H,7H,8H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8-one

Proceeding analogously as described in Example 1, Step 13 butsubstituting1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with3-(4-methoxybenzyl)-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-3H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one provided (250 mg, 19.94%) of the title compound after silicagel column chromatograph with ethyl acetate/petroleum ether (1:1).

Step 2: Synthesis of7-[2-methyl-4-[6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl]phenyl]-1H,5H,6H,7H,8H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8-one

Proceeding analogously as described in Example 39, Step 7 butsubstituting3-(4-methoxybenzyl)-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-3H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one with1-[(4-methoxyphenyl)-methyl]-7-[2-methyl-4-[6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl]phenyl]-1H,5H,6H,7H,8H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8-onegave crude product. Purification by Prep-HPLC under followingconditions: (2 #SHIMADZU (HPLC-01)): Column, XBridge Prep OBD CisColumn, 19*250 mm, 5 um; mobile phase, Water (10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O) and ACN (25% PhaseB up to 37% in 8 min); Detector, UV; gave thetitle compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 442.1; ¹H-NMR:(400 MHz, DMSO-d₆, ppm): δ 9.96 (s, 1H), 8.81-8.83 (d, 1H), 8.56 (s,1H), 8.46-8.49 (m, 2H), 7.55 (d, 1H), 4.83-4.62 (m, 2H), 4.31 (s, 1H),3.94-3.97 (m, 1H), 2.35 (s, 3H).

Example 41 Synthesis of2-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)-phenyl)-6,7-dihydro-2H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of7-(4-bromo-2-methylphenyl)-2-methyl-6,7-dihydro-2H-[1,2,3]triazolo-[4,5-f][1,4]oxazepin-8(5H)-one

To a stirred solution of7-(4-bromo-2-methylphenyl)-3H,5H,6H,7H,8H-[1,2,3]triazolo-[4,5-f]-[1,4]oxazepin-8-one(6.2 g, 19.19 mmol, 1 equiv) in DMF (120 mL) were added K₂CO₃ (5.3 g,38.37 mmol, 2 equiv) and Mel (3.0 g, 21.10 mmol, 1.1 equiv). Theresulting mixture was stirred for overnight at 50° C. under nitrogenatmosphere. The reaction was quenched with water and extracted withEtOAc. The combined organic layers were concentrated under reducedpressure. The residue was purified by silica gel column chromatographyusing PE/EtOAc (1:1) as eluent to afford the title compound as a whitesolid.

Step 2: Synthesis of2-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-2H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 1, Step 12 butsubstituting7-(4-bromo-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f]-[1,4]oxazepin-8(5H)-one with7-(4-bromo-2-methylphenyl)-2-methyl-6,7-dihydro-2H-[1,2,3]triazolo-[4,5-f][1,4]-oxazepin-8(5H)-one provided crude product. Silica gel column withdichloromethane/ethyl acetate (1:2) afforded (1.1 g, 50.80%) of thetitle compound as a white solid.

Step 3: Synthesis of2-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)-phenyl)-6,7-dihydro-2H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 5, Step 12 butsubstituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with2-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-2H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one and 6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridinewith 2-chloro-6-(trifluoromethyl)-1,5-naphthyridine provided (58.3 mg,19.72%) of the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺455.2; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 8.79 (d, 1H), 8.70 (d, 1H),8.67 (d, 1H), 8.30 (d, 1H), 8.25 (dd, 2H), 7.51 (d, 1H), 4.72 (t, 2H),4.29 (d, 1H), 3.97 (s, 1H), 3.61 (s, 3H), 2.33 (s, 3H).

Example 42 Synthesis of2-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-2H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced2-methyl-7-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H,5H,6H,7H,8H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8-one(400 mg, 1.041 mmol, 1 equiv),2-chloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine (364.74 mg, 1.562mmol, 1.5 equiv), K₂CO₃ (431.62 mg, 3.123 mmol, 3 equiv), t-BuOH (2.7mL), H₂O (0.3 mL), and PdAMPHOS (368.56 mg, 0.521 mmol, 0.5 equiv). Theresulting solution was stirred for 12 h at 80° C. The reaction mixturewas then quenched with water. The resulting solution was extracted withethyl acetate and the organic layer was separated and concentrated. Theresidue was applied onto Prep-TLC and eluted withdichloromethane/methanol (10:1). The crude product was purified byre-crystallization from MeOH. This resulted in 52.7 mg (11.12%) of thetitle compound as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 456. ¹H-NMR:(300 MHz, DMSO-d₆, ppm): δ 2.34 (s, 3H), 3.61 (s, 3H), 3.94-3.98 (m,1H), 4.29-4.32 (m, 1H), 4.69-4.73 (m, 2H), 7.54 (d, 1H), 8.47-8.51 (m,3H), 8.83 (d, 1H), 9.97 (s, 1H).

Example 43 Synthesis of2-methyl-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-2H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced2-methyl-7-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H,5H,6H,7H,8H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8-one(400 mg, 1.041 mmol, 1 equiv), 2-chloro-6-(trifluoromethyl)quinazoline(363.19 mg, 1.562 mmol, 1.5 equiv), K₂CO₃ (431.62 mg, 3.123 mmol, 3equiv), toluene (3 mL), EtOH (1.5 mL), and Pd(PPh₃)₄ (180.44 mg, 0.156mmol, 0.15 equiv). The resulting solution was stirred for 12 h at 80° C.The reaction was then quenched with water and extracted with ethylacetate and the organic layer was concentrated under vacuum. The residuewas applied onto Prep-TLC and eluted with dichloromethane/methanol(20:1). The crude product was purified by re-crystallization from MeOHto give the title compound (111.8 mg, 23.63%) as a white solid. LC-MS:(ES, m/z): [M+H]⁺ 455. ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 2.33 (s, 3H),3.61 (s, 3H), 3.89 (m, 1H), 4.20-4.29 (m, 1H), 4.69-4.73 (m, 2H), 7.50(d, 1H), 8.25 (m, 2H), 8.48 (d, 1H), 8.52 (s, 1H), 8.71 (s, 1H), 9.89(s, 1H).

Example 44 Synthesis of6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of methyl4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate

To a stirred solution/mixture of methyl4-bromo-1H-pyrazole-5-carboxylate (100 g, 487.78 mmol, 1 equiv) and3,4-dihydro-2H-pyran (53.3 g, 633.63 mmol, 1.30 equiv) in DCM (1000 mL)was added CF₃COOH (83.4 g, 731.43 mmol, 1.50 equiv) at room temperatureunder nitrogen atmosphere. The resulting mixture was stirred for 6 h atroom temperature and then quenched with sat. NaHCO₃ (aq.). The aqueouslayer was extracted with CH₂Cl₂ and the resulting mixture was washedwith H₂O and was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography, eluting with PE/EtOAc(15:1) to afford the title compound (137 g, 97.14%) as a yellow liquid.

Step 2: Synthesis of4-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylic acid

Into a 500-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced methyl4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylate (22 g,76.09 mmol, 1 equiv), phenylmethanol (110 mL), Cs₂CO₃ (74.4 g, 228.35mmol, 3.00 equiv), and CuCl₂ (1.0 g, 7.61 mmol, 0.1 equiv). Theresulting solution was stirred overnight at 130° C. and then quenchedwith water. The resulting solution was extracted with ethyl acetate andthe aqueous layers were combined. The pH value of the solution wasadjusted to 4 with CH₃COOH (2 mol/L) and the resulting solution wasextracted with ethyl acetate. The organics were removed and the residuewas applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:2) to give (5.1 g, 22.17%) of the titlecompound as a white solid.

Step 3: Synthesis of4-(benzyloxy)-N-(4-bromo-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced4-(benzyloxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxylic acid(5.1 g, 16.87 mmol, 1 equiv), 4-bromo-2-methylaniline (3.1 g, 16.87mmol, 1 equiv), HATU (9.6 g, 25.30 mmol, 1.5 equiv), DMF (50.0 mL), andDIEA (4.4 g, 33.74 mmol, 2 equiv). The resulting solution was stirredovernight at 40° C. and then quenched with water. The resulting solutionwas extracted with ethyl acetate and the organic layers were combinedand then concentrated. The residue was applied onto a silica gel columnand eluted with ethyl acetate/petroleum ether (1:5) to give (5.2 g,65.54%) of the title compound as a white solid.

Step 4: Synthesis ofN-(4-bromo-2-methylphenyl)-4-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide

Into a 25-mL round-bottom flask purged and maintained under H₂atmosphere, were placed4-(benzyloxy)-N-(4-bromo-2-methylphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide(5.2 g, 10.4 mmol, 1 equiv), THF (100 mL), and Pd/C (520 mg). Theresulting solution was stirred for 1 h at room temperature. Then themixture was filtrated to remove Pd/C and the filtrate was concentratedto give the title compound (3.8 g, 90.48%) as a white solid.

Step 5: Synthesis ofN-(4-bromo-2-methylphenyl)-4-(2-oxopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide

Into a 100-mL 3-necked round-bottom flask, were placedN-(4-bromo-2-methylphenyl)-4-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide(3.8 g, 9.99 mmol, 1 equiv), 1-bromopropan-2-one (1.4 g, 10.2 mmol, 1equiv), Na₂CO₃ (3.2 g, 30.19 mmol, 3.02 equiv), and DMF (40 mL). Theresulting solution was stirred for 1 h at room temperature and thenquenched with water. The resulting solution was extracted with ethylacetate. The residue was applied onto a silica gel column and elutedwith EA:PE (1:5) to give the title compound (3.3 g, 75.68%) as a solid.

Step 6: Synthesis ofN-(4-bromo-2-methylphenyl)-4-(2-hydroxypropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wereplacedN-(4-bromo-2-methylphenyl)-4-(2-oxopropoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide(3.1 g, 7.11 mmol, 1 equiv), and MeOH (30 mL, 740.97 mmol, 104.29equiv), and NaBH₄ (0.3 g, 7.93 mmol, 1.12 equiv) was added at 0° C. Theresulting solution was stirred for 2 h at room temperature and thenquenched with NH₄Cl. The resulting solution was extracted with ethylacetate, and the organic layer was dried over anhydrous sodium sulfateand concentrated under vacuum to give 3.1 g of the title compound as acrude product.

Step 7: Synthesis of1-((5-((4-bromo-2-methylphenyl)carbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)propan-2-ylmethanesulfonate

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, wereplacedN-(4-bromo-2-methylphenyl)-4-(2-hydroxy-propoxy)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carboxamide(3 g, 6.84 mmol, 1 equiv), DCM (30 mL, 471.90 mmol, 68.95 equiv), andEt₃N (1.0 g, 9.88 mmol, 1.44 equiv), and MsCl (1.2 g, 10.27 mmol, 1.50equiv) was added dropwise at 0° C. The resulting solution was stirredfor 1 h at room temperature and then quenched with water. The resultingsolution was extracted with dichloromethane, dried over anhydrous sodiumsulfate, and concentrated under vacuum to give 3.7 g of the titlecompound as a crude product.

Step 8: Synthesis of7-(4-bromo-2-methylphenyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 50-mL 3-necked round-bottom flask, were placed1-((5-((4-bromo-2-methyl-phenyl)carbamoyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxy)propan-2-ylmethanesulfonate (3.7 g, 7.16 mmol, 1 equiv), EtOH (40 mL), and t-BuOK(1.6 g, 14.26 mmol, 1.99 equiv). The resulting solution was stirredovernight at 50° C. The reaction was then quenched with NH₄Cl and theresulting mixture was concentrated to remove EtOH. The resultingsolution was extracted with ethyl acetate and the organic layers wascombined and concentrated. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:5) to give (2.1g, 69.73%) of the title compound as a white solid.

Step 9: Synthesis of6-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 5, Step 11 but substituting7-(4-bromo-2,5-dimethylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]-oxazepin-8(5H)-one with7-(4-bromo-2-methylphenyl)-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided crude product. Silica gel column with ethylacetate/petroleum ether (1:2) afforded (1.3 g, 55.41%) of the titlecompound as a grey solid.

Step 10: Synthesis of6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 2, Step 11 but substituting3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one with6-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided crude product. Purification by prep-TLC withdichloromethane/methanol (20:1) as eluent gave (212 mg, 61.73%) thetitle compound as a white solid.

Step 11: Synthesis of6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 8-mL sealed tube, were placed6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (210 mg, 0.39 mmol, 1 equiv), dioxane (2 mL, 23.61 mmol, 60.43equiv), and HCl (2 mL, 65.82 mmol, 168.49 equiv). The resulting solutionwas stirred for 2 h at room temperature and then quenched with NaHCO₃.The resulting solution was extracted with ethyl acetate. After removingthe organics, the residue was applied onto a silica gel column andeluted with dichloromethane/methanol (20:1) to give (86 mg, 48.55%) ofthe title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 454.3;¹H-NMR: (300 MHz, DMSO-d₆): δ 13.15-13.31 (m, 1H), 9.88 (s, 1H), 8.70(s, 1H), 8.45-8.56 (m, 2H), 8.26 (t, 2H), 7.24-7.52 (m, 2H), 4.55-4.60(m, 1H), 4.29-4.49 (m, 1H) 4.18-4.25 (m, 1H), 2.29 (s, 3H), 1.29-1.42(m, 2H), 1.19-1.25 (m, 2H).

Example 45 Synthesis of6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 2, Step 11 but substituting3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one with6-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided crude product. Purification by pre-TLC by eluting withethyl acetate/petroleum ether (1:2) provided the title compound (210 mg,91.72%) as a white solid.

Step 2: Synthesis of6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 44, Step 11 but substituting6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided the title compound (105 mg, 59.28%) as a white solid.LC-MS: (ES, m/z): [M+1]⁺ 454.3; ¹H-NMR: (300 MHz, DMSO-d6): δ 13.17 (d,1H), 8.78 (d, 1H), 8.65 (d, 1H), 8.58-8.59 (m, 1H), 8.33 (s, 1H),8.22-8.30 (m, 2H), 7.41-7.53 (m, 2H), 4.55-4.59 (m, 1H), 4.22-4.42 (m,1H), 3.89-4.19 (m, 1H), 2.28 (d, 3H), 1.32-1.37 (d, 2H), 1.25 (d, 2H).

Example 46 Synthesis of6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 2, Step 11 but substituting3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one with6-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided crude product. Purification by pre-TLC by elutingsilica gel column chromatography by eluting with ethyl acetate/petroleumether (1:1) provided the title compound (110 mg, 19.18%) as a whitesolid.

Step 2: Synthesis of6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 44, Step 11 but substituting6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-pyrido[3,2-d]pyrimidin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided the title compound (22.9 mg, 24.67%) as a white solid.LC-MS: (ES, m/z): [M+1]⁺ 455.1; ¹H-NMR: (300 MHz, DMSO-d₆): δ13.18-13.25 (m, 1H), 9.98 (s, 1H), 8.83 (d, 1H), 8.47-8.44 (m, 3H),7.44-7.58 (m, 2H), 4.61-4.63 (m, 1H), 4.26-4.59 (m, 1H), 3.93-4.23 (m,1H), 2.32 (d, 3H), 1.22-1.32 (m, 3H).

Example 47 Synthesis of2-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 1, Steps 6 to 13 but substituting4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid with methyl4-bromo-1-methyl-1H-pyrazole-3-carboxylate provided the title compoundas a white solid. LC-MS: (ES, m/z): [M+H]⁺ 455.1; ¹H-NMR: (300 MHz,DMSO-d₆, ppm): δ 2.30 (s, 3H), 3.86 (s, 3H), 3.96 (s, 2H), 4.39-4.50 (m,2H), 7.46 (d, 1H), 7.64 (s, 1H), 8.45-8.49 (m, 2H), 8.54 (s, 1H), 8.82(d, 1H), 9.96 (s, 1H).

Example 48 Synthesis of2-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 5, Step 12 but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with2-methyl-7-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2H,5H,6H,7H,8H-pyrazolo[3,4-f][1,4]oxazepin-8-onegave crude product. Purification by silica gel column withdichloromethane/methanol (10:1) as eluent, followed by re-crystallizedfrom MeOH gave the title compound as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 454.1; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 2.30 (s, 3H), 3.86 (s,3H), 3.90-3.97 (m, 2H), 4.39-4.54 (m, 2H), 7.43 (d, 1H), 7.63 (s, 1H),8.21-8.25 (m, 2H), 8.30 (s, 1H), 8.60 (d, 1H), 8.69 (d, 1H), 8.79 (d,1H).

Example 49 Synthesis of1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepine

Step 1: Synthesis of1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepine

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (500 mg, 1.305 mmol, 1 equiv) and THF (5 mL). LiAlH₄ (54.47 mg,1.435 mmol, 1.10 equiv) was added in portions at 0° C. The resultingsolution was stirred overnight at room temperature and then quenchedwith NaOH (1M). The pH value of the solution was adjusted to 5 with HCl(1M) and the resulting solution was extracted with ethyl acetate. Theorganic layers were combined and concentrated under vacuum. The residuewas applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:1) to give the title compound (63 mg, 13.08%)as a white solid.

Step 2: Synthesis of1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepine

Into an 8-mL vial under N₂ atmosphere, were placed1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepine(63 mg, 0.171 mmol, 1 equiv),2-chloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine (59.78 mg, 0.256mmol, 1.5 equiv), K₃PO₄ (72.43 mg, 0.341 mmol, 2 equiv), dioxane (0.5mL), H₂O (0.1 mL), and Pd(DtBPF)Cl₂ (11.12 mg, 0.017 mmol, 0.1 equiv).The resulting solution was stirred for overnight at 80° C. and thendiluted with H₂O. The resulting solution was extracted with ethylacetate and the organic layers were combined and concentrated in vacuum.The residue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:1) to give the title compound (37.6 mg,50.04%) as a yellow solid. LC-MS: (ES, m/z): [M+H]⁺ 441; ¹H-NMR: (300MHz, DMSO-d₆ ppm): δ 9.88 (s, 1H), 8.73 (d, 1H), 8.45-8.40 (m, 3H), 7.27(d, 1H), 7.14 (s, 1H), 4.34 (s, 2H), 4.10-4.07 (m, 2H), 3.75 (s, 3H),3.49 (s, 2H), 2.44 (s, 3H).

Example 50 Synthesis of1-methyl-7-(4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of1-methyl-7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1h-pyrazolo[3,4-f][1,4]oxazepin-8 (5 h)-one

Proceeding as described in Example 1, Steps 6 to 12 to but substituting4-bromo-2-methylaniline with 4-bromoaniline in Step 8 provided the titlecompound as a white solid.

Step 2: Synthesis of1-methyl-7-(4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

To a stirred solution/mixture of1-methyl-7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (300 mg, 0.815 mmol, 1 equiv) and2-chloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine (209.32 mg, 0.896mmol, 1.1 equiv) in dioxane (3 mL) were added K₃PO₄ (345.86 mg, 1.629mmol, 2 equiv), H₂O (0.6 mL) and Pd(DtBPF)Cl₂ (106.19 mg, 0.163 mmol,0.20 equiv) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for 4 h at 100° C. under nitrogen atmosphere andthen diluted with water. The aqueous layer was extracted with EtOAc andthe resulting mixture was concentrated under vacuum. The residue waspurified by Prep-TLC (CH₂Cl₂/MeOH 80:1) to afford the title compound(141.3 mg, 39.47%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 441;¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 9.96-9.96 (d, 1H), 8.81 (d, 1H),8.63-8.67 (m, 2H), 8.47 (d, 1H), 7.59-7.64 (m, 2H), 7.36 (s, 1H),4.51-4.53 (m, 2H), 4.14-4.15 (t, 2H), 4.02 (s, 3H).

Example 51 Synthesis of7-(4-(6-fluoropyrido[3,2-d]pyrimidin-2-yl)-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of 2-bromo-6-fluoropyridin-3-amine

Into a 2000-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced 6-fluoropyridin-3-amine (24.5 g, 218.541 mmol, 1 equiv) and EA(1200 mL, 12258.087 mmol, 56.09 equiv) and NBS (40.84 g, 229.468 mmol,1.05 equiv) was added at −10° C. The resulting solution was stirred for1 h at −10° C. and then quenched with water. The resulting solution wasextracted with ethyl acetate, dried over anhydrous sodium sulfate andconcentrated to give the title compound (20 g, 47.91%) as a yellowsolid.

Step 2: Synthesis of 3-amino-6-fluoropicolinonitrile

Into a 500-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced 2-bromo-6-fluoropyridin-3-amine (10 g, 52.355 mmol, 1 equiv),CuCN (14.07 g, 157.066 mmol, 3 equiv), and DMSO (200 mL). The resultingsolution was stirred for 2 h at 120° C. and then quenched with water.The solids were filtered out and the resulting solution was extractedwith ethyl acetate and the organic layer was concentrated. The residuewas applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1:5) to give the title compound (7 g, 97.51%)of as yellow solid.

Step 3: Synthesis of 2-(aminomethyl)-6-fluoropyridin-3-amine

Into an 8-mL sealed tube under N₂ atmosphere, were placed3-amino-6-fluoropicolinonitrile (200 mg), BH₃-THF (1M) (3 ml), and THF(1 ml). The resulting solution was stirred for 30 min at 10° C. and thenquenched with MeOH. The resulting mixture was concentrated and theresidue was applied onto Prep-TLC and eluted withdichloromethane/methanol (10:1) to give the title compound (100 mg) asyellow solid.

Step 4: Synthesis of7-(4-(6-fluoropyrido[3,2-d]pyrimidin-2-yl)-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 20-mL sealed tube under N₂ atmosphere, were placed3-methyl-4-[1-methyl-8-oxo-1H,5H,6H,7H,8H-pyrazolo[3,4-f][1,4]oxazepin-7-yl]benzaldehyde(200 mg, 0.701 mmol, 1 equiv), 2-(aminomethyl)-6-fluoropyridin-3-amine(98.95 mg, 0.701 mmol, 1 equiv), and MeOH (7 mL PhI(OAc)₂ (451.45 mg,1.402 mmol, 2 equiv). The resulting solution was stirred for 1 h at 25°C. and then concentrated. The residue was applied onto Prep-TLC andeluted with dichloromethane/methanol (30:1) to give the title compound(144.8 mg, 51.08%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 405;¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 2.32 (s, 3H), 3.98 (s, 5H), 4.45-4.56(m, 2H), 7.35 (s, 1H), 7.46 (d, 1H), 7.91 (d, 1H), 8.41 (d, 1H), 8.47(s, 1H), 8.68-8.72 (m, 1H), 9.64 (s, 1H).

Example 52 Synthesis of7-(4-(6-fluoro-1,5-naphthyridin-2-yl)-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of ethyl (E)-3-(3-amino-6-fluoropyridin-2-yl)acrylate

To a stirred mixture of 2-bromo-6-(trifluoromethyl)pyridin-3-amine (1.00g, 4.149 mmol, 1.00 equiv) and ethyl prop-2-enoate (0.83 g, 8.298 mmol,2.00 equiv) in DMF (20.00 mL) were added P(o-tol)₃ (0.25 g, 0.830 mmol,0.20 equiv), Et₃N (1.26 g, 12.448 mmol, 3.00 equiv) and Pd(OAc)₂ (0.09g, 0.415 mmol, 0.10 equiv). The resulting mixture was stirred forovernight at 100° C. under nitrogen atmosphere. The reaction mixture wasquenched with water at room temperature. The resulting mixture wasextracted with EtOAc and the combined organic layers was washed withNaCl (aq.) and then concentrated under reduced pressure. The residue waspurified by silica gel column chromatography with PE/EtOAc (20:1) aseluent to afford the title compound (550 mg, 50.94%) as a yellow solid.

Step 2: Synthesis of 6-fluoro-1,5-naphthyridin-2 (1H)-one

Into a 100 mL 3-necked round-bottom flask, were placed ethyl(E)-3-(3-amino-6-fluoropyridin-2-yl)acrylate (550.00 mg, 2.114 mmol,1.00 equiv), dioxane (3.00 mL), and HCl (3.00 mL). The resultingsolution was stirred overnight at 100° C. The resulting mixture wasdiluted with water and the solids were collected by filtration to givethe title compound (400 mg, 88.37%) as a grey solid.

Step 3: Synthesis of 6-fluoro-1,5-naphthyridin-2-yltrifluoromethanesulfonate

An ice water bath-cooled solution of 6-fluoro-1,5-naphthyridin-2(1H)-one (350 mg, 2.132 mmol, 1 equiv) and TEA (431.54 mg, 4.265 mmol, 2equiv) in DCM (17.5 mL) was mixed with a solution oftrifluoromethanesulfonyl trifluoromethanesulfonate (721.92 mg, 2.559mmol, 1.20 equiv) in DCM (4 mL) over 20 mins. The resulting mixture thenwas stirred for 2 h at 0° C. The reaction was quenched with sat. NaHCO₃(aq.) at room temperature and the resulting mixture was extracted withCH₂Cl₂. The combined organic layers were dried over anhydrous Na₂SO₄.After filtration, the filtrate was concentrated under reduced pressureand the crude product was used in the next step directly without furtherpurification.

Step 4: Synthesis of7-(4-(6-fluoro-1,5-naphthyridin-2-yl)-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 5, Step 12 but substituting7-(2,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with7-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H,5H,6H,7H,8H-pyrazolo[3,4-f][1,4]oxazepin-8-and6-chloro-4-methyl-2-(trifluoromethyl)-1,5-naphthyridine with6-fluoro-1,5-naphthyridin-2-yl trifluoromethanesulfonate gave crudeproduct. The crude product was purified by silica gel columnchromatography with PE/EtOAc (2:1) as eluent, followed by Prep-TLC(CH₂Cl₂/MeOH 40:1) and re-crystallization from MeOH (3 mL) to afford thetitle compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 404; ¹H-NMR:(300 MHz, DMSO-d₆, ppm): δ 8.67 (t, 1H), 8.34-8.48 (m, 1H), 8.24 (d,1H), 8.16 (dd, 1H), 7.63-7.67 (m, 1H), 7.45 (d, 1H), 7.37 (s, 1H),4.45-4.58 (m, 2H), 4.0 (d, 5H), 2.32 (s, 3H).

Example 53 Synthesis of7-(4-(6-fluoroquinazolin-2-yl)-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of 6-fluoroquinazoline-2,4 (1H,3H)-dione

Into a 250-mL 3-necked round-bottom flask purged and maintained withCO₂, were placed 2-amino-5-fluorobenzonitrile (3 g, 22.038 mmol, 1equiv), DMF (90 mL, 1162.958 mmol, 52.77 equiv), and DBU (10.06 g,66.081 mmol, 3.00 equiv). The resulting solution was stirred forovernight at 100° C. and then diluted with H₂O. The pH value of thesolution was adjusted to 5 with HCl (1 mol/L) and the resulting mixturewas filtered, The solids were washed with H₂O and dried to give (3.6 g,90.68%) of the title compound as a yellow solid.

Step 2: Synthesis of 2,4-dichloro-6-fluoroquinazoline

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced 6-fluoroquinazoline-2,4 (1H,3H)-dione (3.6 g, 19.985 mmol, 1equiv), POCl₃ (36.01 mL), and PCl₅ (20.81 g, 99.933 mmol, 5.00 equiv).The resulting solution was stirred overnight at 120° C. and thenconcentrated under vacuum. The resulting solution was diluted with ofH₂O and extracted with dichloromethane. The organic layers werecombined, washed with K₃PO₄. The mixture was concentrated under vacuumto give the title compound (2.6 g, 72.22%) as a yellow solid.

Step 3: Synthesis of 2-chloro-6-fluoroquinazoline

Into a 50-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced 2,4-dichloro-6-fluoroquinazoline (2.6 g, 11.980 mmol, 1 equiv),Pd(PPh₃)₄ (1.38 g, 1.198 mmol, 0.1 equiv), PPh₃ (4.71 g, 17.971 mmol,1.5 equiv), THF (26.00 mL), and Bu₃SnH (3.85 g, 13.179 mmol, 1.1 equiv).The resulting solution was stirred overnight at room temperature andthen concentrated under vacuum. The residue was applied onto a silicagel column and eluted with ethyl acetate/petroleum ether (1:50) to givethe title compound (1.2 g, 54.86%) as a white solid.

Step 4: Synthesis of7-(4-(6-fluoroquinazolin-2-yl)-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 50, Step 2, but substituting2-chloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine with2-chloro-6-fluoroquinazoline (200 mg, 1.095 mmol, 1 equiv) and1-methyl-7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with1-methyl-7-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1H,5H,6H,7H,8H-pyrazolo[3,4-f][1,4]-oxazepin-8-oneprovided the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺404.2; ¹H-NMR: (400 MHz, DMSO-d6, ppm): δ 9.70 (s, 1H), 8.49 (d, 1H),8.42 (m, 1H), 8.15-8.18 (m, 1H), 7.99-8.01 (m, 2H), 7.36 (s, 2H),4.46-4.56 (m, 2H), 3.98-4.00 (m, 5H), 2.49-2.51 (m, 3H).

Example 54 Synthesis of4-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one

Step 1: Synthesis of 3-(2-(benzyloxy)ethoxy)picolinic acid

To a stirred solution of methyl 3-bromopyridine-2-carboxylate (9.4 g,43.512 mmol, 1 equiv) in 2-(benzyloxy)ethan-1-ol (50 mL) was addedt-BuOLi (17.42 g, 217.558 mmol, 5 equiv) and Cu(OAc)₂ (1.58 g, 8.702mmol, 0.2 equiv) in portions at room temperature under nitrogenatmosphere. The resulting mixture was stirred overnight at 130° C. undernitrogen atmosphere. The mixture was allowed to cool down to roomtemperature and then extracted with EtOAc. The aqueous layer wascollected and acidified to pH 4 with HCl (aq.) and extracted with EtOAc.The organic layer was collected and concentrated and the residue waspurified by silica gel column chromatography by eluting with CH₂Cl₂/MeOH(20:1) to afford the title compound (5 g, 42%) as a white solid.

Step 2: Synthesis of3-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)picolinamide

To a stirred solution of 3-(2-(benzyloxy)ethoxy)picolinic acid (4.4 g,16.100 mmol, 1 equiv) and 4-bromo-2-methylaniline (3.00 g, 16.100 mmol,1 equiv) in DCM (44 mL, 692.122 mmol, 42.99 equiv) were added DIEA (4.16g, 32.200 mmol, 2 equiv) and HATU (9.18 g, 24.150 mmol, 1.5 equiv) inportions at room temperature under nitrogen atmosphere. The resultingmixture was stirred for overnight at room temperature under nitrogenatmosphere and then extracted with EtOAc. After filtration, the filtratewas concentrated under reduced pressure. The residue was purified bysilica gel column chromatography by eluting with CH₂Cl₂/MeOH (50:1) toafford the title compound (4.3 g, 61%) as a white solid.

Step 3: Synthesis of4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one

Proceeding analogously as described in Example 1, Steps 9 to 12 butsubstituting4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamidewith 3-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)picolinamideprovided the title compound as a white solid.

Step 4: Synthesis of4-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one

Proceeding as described in Example 2, Step 11 but substituting3-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-pyrazolo[1,5-a]pyrazin-4(5H)-one with4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4-dihydropyrido[2,3-f][1,4]oxazepin-5(2H)-one provided crude product. Purification by TLC with CH₂Cl₂/MeOH(20:1) as eluent gave the title compound as a white solid. LC-MS: (ES,m/z): [M+H]⁺ 451.2; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 9.92 (s, 1H),8.74 (s, 1H), 8.59 (s, 1H), 8.52-8.51 (m, 2H), 8.30 (m, 2H), 7.68-7.65(m, 2H), 7.62 (d, 1H), 4.47-4.45 (m, 2H), 3.94-3.92 (m, 2H), 2.38 (s,3H).

Example 55 Synthesis of8-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-7,8-dihydropyrimido[4,5-f][1,4]oxazepin-9(6H)-one

Step 1: Synthesis of 5-(2-(benzyloxy)ethoxy)pyrimidine-4-carboxylic acid

To a stirred solution of 5-bromopyrimidine-4-carboxylic acid (4.3 g,21.183 mmol, 1 equiv) and 2-(benzyloxy)ethan-1-ol (25 mL) were addedK₂CO₃ (8.78 g, 63.548 mmol, 3 equiv) and CuBr₂ (0.95 g, 4.237 mmol, 0.2equiv) at room temperature under nitrogen atmosphere. The resultingmixture was stirred for overnight at 100° C. under nitrogen atmosphere.The mixture was acidified to pH 5 with HCl (aq.) and extracted with EA.The residue was purified by silica gel column chromatography, elutedwith CH₂Cl₂/MeOH (10:1) to afford PH-IDE-0637-1 (1.0 g, 17%) as a whitesolid.

Step 2: Synthesis of5-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)pyrimidine-4-carboxamide

Proceeding analogously as described in Example 54, Step 2 butsubstituting 3-(2-(benzyloxy)ethoxy)picolinic acid with5-(2-(benzyloxy)ethoxy)pyrimidine-4-carboxylic acid and4-bromo-2-methylaniline provided crude product. Purification by silicagel column chromatography, eluting with CH₂Cl₂/MeOH (10:1) provided thetitle compound as a white solid.

Step 3: Synthesis of8-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7,8-dihydropyrimido[4,5-f][1,4]oxazepin-9(6H)-one

Proceeding analogously as described in Example 1, Steps 9 to 12 butsubstituting4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamidewith5-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)pyrimidine-4-carboxamideto a stirred solution of8-(4-bromo-2-methylphenyl)-7,8-dihydropyrimido[4,5-f][1,4]oxazepin-9(6H)-one provided the title compound as a white solid.

Step 4: Synthesis of8-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-7,8-dihydropyrimido[4,5-f][1,4]oxazepin-9(6H)-one

Proceeding analogously as described in Example 50, Step 2, butsubstituting1-methyl-7-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with8-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-7,8-dihydropyrimido[4,5-f][1,4]oxazepin-9(6H)-one provided crude product. Purification by Prep-TLC (CH₂Cl₂/MeOH20:1) provided the title compound as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 452.2; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 9.92 (s, 1H), 9.10 (s,1H), 8.81 (s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.52-8.51 (d, 1H), 8.30(t, 2H), 7.57 (d, 1H), 4.66-4.62 (m, 2H), 4.08-4.04 (m, 2H), 2.36 (s,3H).

Example 56 Synthesis of ethyl3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate

Step 1: Synthesis of2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (200 mg, 0.457 mmol, 1 equiv) in AcOH (2 mL) was added Br₂ (511mg, 3.201 mmol, 7 equiv) dropwise at 0° C. under nitrogen atmosphere.The resulting mixture was stirred for overnight at 60° C. under nitrogenatmosphere. The resulting mixture was concentrated under reducedpressure and the resulting mixture was extracted with EtOAc and driedover anhydrous Na₂SO₄. After filtration, the filtrate was concentratedunder reduced pressure to afford the title compound (127 mg, 54%) as awhite solid.

Step 2: Synthesis of ethyl3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate

To a stirred solution of2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)-phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (3.1 g, 6.004 mmol, 1 equiv) and Pd(dppf)Cl₂ (0.88 g, 1.201mmol, 0.2 equiv) in EtOH (31 mL) was added TEA (1.82 g, 18.012 mmol, 3equiv) at room temperature under CO atmosphere. The resulting mixturewas stirred for overnight at 80° C. under CO atmosphere and thenconcentrated under vacuum. The residue was purified by silica gel columnchromatography but eluting with PE/EA (1:1) to afford the title compound(1.2 g, 39%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 510.3; ¹H-NMR:(400 MHz, DMSO-d₆, ppm): δ 9.91 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H),8.50 (d, 1H), 8.29 (t, 2H), 7.58-7.56 (d, 1H), 4.65 (t, 2H), 4.34-4.29(m, 3H), 4.00-3.96 (m, 1H), 2.67 (s, 3H), 2.36 (s, 3H), 1.32 (t, 3H).

Example 57 Synthesis of2-(hydroxymethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, was placedethyl3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate(396 mg, 0.78 mmol, 1.00 equiv), oxolane (8 mg), and NaBHEt₃ (1 M) (3.11mL, 4.00 mmol). The resulting solution was stirred for 3 h at −78° C. ina liquid nitrogen bath and then quenched with water/ice. The resultingsolution was extracted with ethyl acetate, dried over anhydrous sodiumsulfat, and concentrated. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1/1) to give thetitle compound (12.0 mg) as a white solid. LC-MS: (ES, m/z): [M+H]⁺468.2; ¹H-NMR-PH-IDE-0645-0: (300 MHz, DMSO-d₆, ppm): δ 9.91 (s, 1H),8.73 (s, 1H), 8.55 (s, 1H), 8.50 (d, 1H), 8.29 (s, 2H), 7.54 (d, 1H),5.02 (t, 1H), 4.44 (m, 4H), 4.25 (m, 1H), 3.89 (m, 1H), 2.34 (s, 3H),2.27 (s, 3H)

Example 58 Synthesis of2-(1-hydroxyethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-2-vinyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 25-mL round-bottom flask under N₂ atmosphere, were placed2-bromo-3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)-quinazolin-2-yl]phenyl]-3H,3aH,4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(50 mg, 0.10 mmol, 1.00 equiv), tributyl(ethenyl)stannane (79 mg, 0.25mmol, 2.50 equiv), tetrakis(triphenylphosphane) palladium (23 mg, 0.02mmol, 0.20 equiv), and toluene (0.50 mL). The flask was wrapped withaluminum foil and the resulting solution was stirred for 12 h at 110° C.in an oil bath. The reaction was then quenched with water and theresulting solution was diluted with EA. The solids were filtered out andthe resulting solution was extracted with ethyl acetate. The organicphase was dried over anhydrous sodium sulfate and after concentration,the residue was applied onto a silica gel column and eluted with ethylacetate/petroleum ether (1/1) to give the title compound (38 mg) as awhite solid.

Step 2: Synthesis of2-(1,2-dihydroxyethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)-phenyl)-2-vinyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (38.00 mg, 0.082 mmol, 1.00 equiv), THF (0.60 mL, 1.00 equiv),H₂O (0.20 mL), NMO (38.00 mg, 0.330 mmol, 4.00 equiv), and OsO₄ (8.00mg, 0.033 mmol, 0.40 equiv) at 0° C. The resulting solution was stirredfor 4 h at room temperature and then quenched with water. The resultingsolution was extracted with ethyl acetate and the organic phase waswashed with brine. The mixture was dried over anhydrous sodium sulfateand concentrated to give the title compound (36 mg, 80%) as a whitesolid.

Step 3: Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere were placed2-(1,2-dihydroxyethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (38.00 mg, 0.082 mmol, 1.00 equiv), dioxane (0.40 mL), H₂O(0.20 mL), and NaIO₄ (35.00 mg, 0.164 mmol, 2.0 equiv) at 0° C. Theresulting solution was stirred for 1 h at room temperature and thenquenched with water. The resulting solution was extracted with ethylacetate and the organic phase was washed with brine. The organic layerwas dried over anhydrous sodium sulfate, filtered and concentrated togive the title compound (28 mg, 90%) as a white solid.

Step 4: Synthesis of2-(1-hydroxyethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, were placed3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde(50 mg, 0.10 mmol, 1.00 equiv) and THF (0.5 mL) was added at 0° C.Chloro(methyl)magnesium (0.30 mL, 0.30 mmol, 3.00 equiv) was added andthe the resulting solution was stirred for 3 h at 0° C. in a water/icebath. The reaction was then quenched with water/ice and extracted withethyl acetate. The organic phase was dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1/1) togive the title compound (24.2 mg) as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 482; ¹H-NMR: (300 MHz, DMSO, ppm): δ 9.91 (s, 1H), 8.73 (s, 1H),8.55 (d, 1H), 8.49 (dd, 1H), 8.28 (s, 2H), 7.53 (d, 1H), 5.02-4.84 (m,2H), 4.80 (m, 2H), 4.44 (m, 1H), 3.88 (m, 1H), 2.34 (s, 3H), 2.27 (s,3H), 1.43 (d, 3H).

Example 59 Synthesis of2-(2-hydroxypropan-2-yl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution of ethyl3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate(200 mg, 0.393 mmol, 1 equiv) in THF (2 mL) was added TEA (119.17 mg,1.178 mmol, 3 equiv). MeMgCl (0.39 mL, 1 mol/L, 1 equiv) was addeddropwise at −78° C. with stirring for 30 min. After stirring for 2 h atroom temperature under nitrogen atmosphere, the resulting mixture wasextracted with EtOAc and the organic layer was concentrated. The residuewas purified by Prep-TLC (CH₂Cl₂/MeOH 20:1) to afford the title compound(54.8 mg, 28%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 496.4; ¹H-NMR:(300 MHz, DMSO-d₆, ppm): δ 9.89 (s, 1H), 8.72 (s, 1H), 8.53 (s, 1H),8.48 (d, 1H), 8.27 (s, 2H), 7.53 (d, 1H), 4.91 (s, 1H), 4.45-4.41 (m,1H), 4.31-4.24 (m, 2H), 3.89-3.85 (m, 1H), 2.48 (s, 3H), 2.32 (s, 3H),1.48 (s, 6H).

Example 60 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid

Into a 8-ml sealed tube purged and maintained with an inert atmosphereof argon, were placed ethyl3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)quinazolin-2-yl]phenyl]-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-2-carboxylate(200 mg, 0.404 mmol, 1 equiv), MeOH (2 ml), H₂O (0.3 ml), and NaOH(48.43 mg, 1.211 mmol, 3 equiv). The resulting solution was stirred for1 h at 50° C. in an oil bath and then concentrated under vacuum. The pHvalue of the solution was adjusted to 3-4 with HCl (1.0 mol/l). Thecrude product was purified by re-crystallization from EA to give thetitle compound (140 mg, 73.46%) as a light-yellow solid. LC-MS: (ES,m/z): [M+H]⁺ 482.0; H-HNMR (300 MHz, DMSO, ppm): δ 2.34 (s, 3H), 2.49(s, 3H), 3.93-3.97 (m, 1H), 4.30-4.34 (m, 1H), 4.60 (t, 2H), 7.55 (d,1H), 8.28 (t, 2H), 8.48 (d, 1H), 8.55 (s, 1H), (m, 2H), 8.72 (s, 1H),9.90 (s, 1H), 12.73 (bs, 1H).

Example 61 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-2-(morpholinomethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde(50 mg, 0.10 mmol, 1.00 equiv), oxolane (1 mL), morpholine (87 mg, 1.00mmol, 10.00 equiv), acetic acid (3 mg), and NaBH₃CN (19 mg, 0.30 mmol,3.00 equiv). The resulting solution was stirred for 3 h at roomtemperature and then quenched with water/ice. The resulting solution wasextracted with ethyl acetate, dried over anhydrous sodium sulfate,filtered and the organ layer was concentrated. The residue was appliedonto a silica gel column and eluted with ethyl acetate/hexane (1/1) togive the title compound (28.2 mg) as a white solid. LC-MS: (ES, m/z):[M+H]⁺ 537.2; ¹H-NMR: (400 MHz, DMSO-d₆, ppm δ 9.91 (s, 1H), 8.73 (s,1H), 8.55 (s, 1H), 8.47 (d, 1H), 8.26 (s, 2H), 7.54 (d, 1H), 4.47 (m,2H), 4.27 (m, 1H), 3.89 (m, 1H), 3.55 (m, 4H), 3.47 (s, 2H), 2.39 (d,4H), 2.34 (s, 3H), 2.26 (s, 3H).

Example 62 Synthesis of(3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)(morpholino)methanone

Into a 8-mL sealed tube purged and maintained under nitrogen atmosphere,were placed3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid (70 mg, 0.150 mmol, 1 equiv), morpholine (15.66 mg, 0.180 mmol,1.20 equiv), DMF (1.0 mL), DIEA (38.71 mg, 0.299 mmol, 2 equiv), andHATU (85.41 mg, 0.225 mmol, 1.5 equiv). The resulting solution wasstirred for 12 h at 25° C. and then quenched with water. The resultingsolution was extracted with ethyl acetate and the organic layerscombined and concentrated under vacuum to give the title compound (55mg, 68.45%) as a light-yellow solid. LCMS: (ES, m/z) [M+H]⁺ 551.2;¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 2.30 (s, 6H), 3.58-3.64 (m, 8H),3.92-3.98 (m, 1H), 4.27-4.37 (m, 1H), 4.55 (d, 2H), 7.54 (d, 1H), 8.28(t, 2H), 8.49 (d, 1H), 8.55 (s, 1H), 8.72 (s, 1H), 9.90 (s, 1H).

Example 63 Synthesis of2-((dimethylamino)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 25-mL 3-necked round-bottom flask purged and maintained undernitrogen atmosphere, were placed3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde(50 mg, 0.10 mmol, 1.00 equiv), oxolane (1.50 mL), dimethylamine (0.50mg, 10.0 mmol, 10.0 equiv), acetic acid (3 mg), and NaBH₃CN (19 mg, 3.00mmol, 3.00 equiv). The resulting solution was stirred for 3 h at roomtemperature and then quenched with water/ice. The resulting solution wasextracted with ethyl acetate. The combined organic phase was dried overanhydrous sodium sulfate, filtered and concentrated. The residue wasapplied onto a silica gel column and eluted with ethyl acetate/hexane(1/1) to give (39.2 mg) of the title compound as a white solid. LC-MS:(ES, m/z): [M+H]⁺ 495.2; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 9.91 (s,1H), 8.73 (s, 1H), 8.55 (s, 1H), 8.48 (d, 1H), 8.29 (s, 2H), 7.54 (d,1H), 4.47 (t, 2H), 4.27 (m, 1H), 3.92 (m, 1H), 3.40 (s, 2H), 2.35 (s,3H), 2.25 (s, 3H), 2.17 (s, 6H).

Example 64 Synthesis of3-bromo-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of methyl1-(2-(benzyloxy)ethyl)-4-bromo-1H-pyrazole-5-carboxylate

Into a 500-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced methyl 4-bromo-1H-pyrazole-5-carboxylate (20 g, 97.556 mmol, 1equiv), 2-(benzyloxy)ethan-1-ol (29.69 g, 195.111 mmol, 2 equiv), DIAD(39.45 g, 195.111 mmol, 2 equiv), and THF (200 mL, 2468.598 mmol, 25.30equiv), and PPh₃ (51.17 g, 195.111 mmol, 2 equiv) was added at 0° C. Theresulting solution was stirred for 12 h at 25° C. and then concentrated.The residue was applied onto a silica gel column and eluted withdichloromethane/petroleum ether (1:10) to give the title compound (25 g,75.55%) as a yellow liquid.

Step 2: Synthesis of1-(2-(benzyloxy)ethyl)-4-bromo-1H-pyrazole-5-carboxylic acid

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, were placed methyl1-(2-(benzyloxy)ethyl)-4-bromo-1H-pyrazole-5-carboxylate (25 g, 73.705mmol, 1 equiv), EtOH (200 mL), H₂O (100 mL), and NaOH (8.84 g, 221.116mmol, 3 equiv). The resulting solution was stirred for 12 h at 25° C.The pH value of the solution was adjusted to 5 with HCl and theresulting solution was extracted with ethyl acetate, dried overanhydrous sodium sulfate and concentrated to give the title compound (15g, 62.59%) as a white solid.

Step 3: Synthesis of3-bromo-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 1, Steps 6 to 12, butsubstituting 4-bromo-1-methyl-1H-pyrazole-5-carboxylic acid with1-(2-(benzyloxy)ethyl)-4-bromo-1H-pyrazole-5-carboxylic acid providedthe title compound as a white solid.

Step 4: Synthesis of3-bromo-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 49, Step 2, butsubstituting1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepanewith3-bromo-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one and 2-chloro-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine with2-chloro-6-(trifluoromethyl)quinazoline provided the title compound as ayellow solid. LC-MS: (ES, m/z): [M+H]⁺ 503.9; ¹H-NMR: (300 MHz, DMSO,ppm): δ 9.90 (s, 1H), 8.72 (s, 1H), 8.54 (s, 1H), 8.48 (d, 1H), 8.28 (t,2H), 7.79 (s, 1H), 7.56 (d, 1H), 4.60 (t, 2H), 4.40-4.29 (m, 1H), 3.95(d, 1H), 2.34 (s, 3H).

Example 65 Synthesis of5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylicacid

Step 1: Synthesis of ethyl5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylate

Proceeding analogously as described in Example 56, Step 2, butsubstituting2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo-[1,5-a]pyrazin-4(5H)-one with3-bromo-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one provided the title compound as a light yellow solid.

Step 2: Synthesis of5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylicacid

Proceeding analogously as described in Example 60 but substituting ethyl3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)quinazolin-2-yl]phenyl]-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-2-carboxylatewith ethyl5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylateprovided crude product. The crude product was purified by Prep-TLC(CH₂Cl₂/MeOH 1:1) to afford the title compound as a white solid. LC-MS:(ES, m/z): [M+H]⁺ 468.0; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 14.00 (s,1H), 9.91 (s, 1H), 8.73 (s, 1H), 8.59 (d, 1H), 8.52 (dd, 1H), 8.28 (t,2H), 8.15 (s, 1H), 7.65 (d, 1H), 4.73 (dd, 2H), 4.45 (dt, 1H), 4.12 (dt,1H), 2.41 (s, 3H).

Example 66 Synthesis of5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide

Proceeding analogously as described in Example 62 but substituting3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid with5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylicacid and morpholine with NH₄Cl provided crude product. Purification byPrep-TLC (CH₂Cl₂/MeOH 12:1) provided the title compound as a light brownsolid. LC-MS: (ES, m/z): [M+H]⁺ 467.2; ¹H-NMR: (300 MHz, DMSO-d₆, ppm):δ 9.90 (s, 1H), 9.26 (s, 1H), 8.72 (s, 1H), 8.56 (s, 1H), 8.50 (d, 1H),8.28 (s, 2H), 8.01 (s, 1H), 7.61 (d, 1H), 7.43 (s, 1H), 4.67 (t, 2H),4.37 (dd, 1H), 4.09-3.97 (m, 1H), 3.04 (q, 1H), 2.37 (s, 3H).

Example 67 Synthesis of5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbonitrile

Into a 8-mL sealed tube under N₂ atmosphere, were placed3-bromo-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo-[1,5-a]pyrazin-4(5H)-one (150 mg, 0.299 mmol, 1 equiv), Zn(CN)₂ (70.14 mg, 0.597 mmol, 2equiv), DMF (3 mL), and Pd(PPh₃)₄ (51.76 mg, 0.045 mmol, 0.15 equiv).The resulting solution was stirred for 12 h at 120° C. and then quenchedwith NaHCO₃. The resulting solution was extracted with ethyl acetate andthe organic layer was concentrated. The residue was applied ontoPrep-TLC and eluted with dichloromethane/methanol (40:1) to give thetitle compound (69.4 mg, 51.83%) as a yellow solid. LC-MS: (ES, m/z):[M+H]⁺ 449.3; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 2.38 (s, 3H), 4.01-4.04(m, 1H), 4.37-4.44 (m, 1H), 4.68-4.71 (m, 2H), 7.59 (d, 1H), 8.29 (d,3H), 8.50 (s, 1H), 8.55 (s, 1H), 8.73 (s, 1H), 9.91 (s, 1H).

Example 68 Synthesis of5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3-morpholino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution/mixture of3-bromo-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (100 mg, 0.199 mmol, 1 equiv) and morpholine (86.72 mg, 0.995mmol, 5.00 equiv) in dioxane (2 mL) was added t-BuONa (47.83 mg, 0.498mmol, 2.5 equiv) at room temperature under nitrogen atmosphere. Theresulting mixture was stirred for overnight at 50° C. and then dilutedwith water. The aqueous layer was extracted with EtOAc and the organiclayer was concentrated. The residue was purified by Prep-TLC(CH₂Cl₂/MeOH 80:1) to afford the title compound (51.5 mg, 50.87%) as awhite solid. LC-MS: (ES, m/z): [M+H]⁺ 509.2; ¹H-NMR: (300 MHz, DMSO-d₆,ppm): δ 2.33 (s, 3H), 3.13 (d, 4H), 3.68 (t, 4H), 3.92 (s, 1H), 4.24 (s,1H), 4.50 (t, 2H), 7.38 (s, 1H), 7.53 (d, 1H), 8.29 (s, 2H), 8.48 (d,1H), 8.55 (s, 1H), 8.73 (s, 1H), 9.91 (s, 1H).

Example 69 Synthesis of4-(5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyazolo[1,5-a]pyrazin-3-yl)morpholin-3-one

Into a 25-mL round-bottom flask, were placed3-bromo-5-(2-methyl-4-(6-(trifluoro-methyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (150.00 mg, 0.299 mmol, 1.00 equiv), morpholin-3-one (36.23 mg,0.358 mmol, 1.20 equiv), dioxane (2.00 mL), K₂CO₃ (82.54 mg, 0.597 mmol,2.00 equiv), (1S,2S)-cyclohexane-1,2-diamine (6.82 mg, 0.060 mmol, 0.20equiv), and CuI (5.69 mg, 0.030 mmol, 0.10 equiv). The resultingsolution was stirred for 1 overnight at 110° C. and then quenched withwater. The resulting solution was extracted with dichloromethane and theorganic layer was concentrated. The residue was applied onto a Prep TLCand eluted with ethyl acetate/petroleum ether (1:1) to give the titlecompound (6.2 mg, 3.97%) as a white solid. LC-MS: (ES, m/z): 523.3;¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 2.36 (s, 3H), 3.72-3.75 (m, 2H),3.91-3.94 (m, 3H), 4.17 (s, 2H), 4.33 (s, 1H), 4.60-4.63 (m, 2H), 7.58(d, 1H), 7.71 (s, 1H), 8.30 (s, 2H), 8.51 (d, 1H), 8.56 (s, 1H), 8.74(s, 1H), 9.92 (s, 1H).

Example 70 Synthesis of5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3-(morpholino-methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substituting3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehydewith5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-providedcrude product. The crude product was purified by Prep-TLC (CH₂Cl₂/MeOH40:1), followed by Prep-HPLC using the following conditions (Column:XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; Mobile Phase A:Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 30% B to37% B in 7 min; 254; 220 nm; Rt: 5.08 min) to afford the title compoundas a white solid. LC-MS: (ES, m/z): [M−H]⁺523.4; ¹H-NMR (DMSO, 400 MHz,ppm): δ 9.89 (s, 1H), 8.72 (s, 1H), 8.54 (s, 1H), 8.50 (d, 1H), 88.27(s, 2H), 7.56 (d, 2H), 4.67 (s, 2H), 3.98-4.56 (m, 3H), 3.70-3.95 (m,5H), 2.40 (s, 4H), 2.32 (s, 3H).

Example 71 Synthesis of7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-1-(2-morpholinoethyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 64, Step 1, butsubstituting methyl 4-bromo-1H-pyrazole-5-carboxylate with7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided crude product. Purification by Prep-TLC (CH₂Cl₂/MeOH60:1) gave the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺553.2; ¹H-NMR: (300 MHz, CDCl₃, ppm): δ 9.56 (s, 1H), 8.62 (s, 1H), 8.57(dd, 1H), 8.27 (s, 1H), 8.21 (d, 2H), 8.09 (dd, 1H), 7.30-7.43 (m, 2H),4.73 (t, 2H), 4.49-4.53 (m, 2H), 3.99-4.03 (m, 2H), 3.68 (s, 4H), 2.81(bs, 2H), 2.53 (bs, 4H), 2.41 (s, 3H).

Example 72 Synthesis of1-(2-(4-hydroxypiperidin-1-yl)ethyl)-7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of 2-(4-(benzyloxy)piperidin-1-yl)ethan-1-ol

To a stirred solution/mixture of 4-(benzyloxy)piperidine (500 mg, 2.614mmol, 1 equiv) and 2-bromoethan-1-ol (392.00 mg, 3.137 mmol, 1.20 equiv)in CH₃CN (0.4 mL) was added K₂CO₃ (1083.83 mg, 7.842 mmol, 3.00 equiv)at room temperature under nitrogen atmosphere. The resulting mixture wasstirred for overnight at 90° C. and then quenched with sat. NH₄Cl (aq.).The aqueous layer was extracted with EtOAc and the organic layer wasconcentrated under vacuum. The residue was purified by reverse flashchromatography under following conditions: Column, C18 silica gel;mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV254 nm. The resulting mixture was concentrated and the residue wasextracted with EtOAc. The combined organic layers were dried overanhydrous Na₂SO₄. After filtration, the filtrate was concentrated underreduced pressure to give the title compound (340 mg, 55.27%) as a yellowoil.

Step 2: Synthesis of1-(2-(4-(benzyloxy)piperidin-1-yl)ethyl)-7-(2-methyl-4-(6-(trifluoro-methyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in example 64, Step 1, butsubstituting methyl 4-bromo-1 h-pyrazole-5-carboxylate with7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one and 2-(benzyloxy)ethan-1-ol with2-(4-(benzyloxy)piperidin-1-yl)ethan-1-ol provided crude product.Purification by prep-TLC (CH₂Cl₂/MeOH 100:1) gave the title compound asa white solid.

Step 3: Synthesis of1-(2-(4-hydroxypiperidin-1-yl)ethyl)-7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 1, Step 9, butsubstituting4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamidewith1-(2-(4-(benzyloxy)piperidin-1-yl)ethyl)-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one gave crude product. Purification by prep-TLC (CH₂Cl₂/MeOH50:1), followed by reverse flash chromatography under the followingconditions: Column, C18 silica gel; mobile phase, MeOH in water, 10% to50% gradient in 10 min; detector, UV 254 nm, provided the title compoundas a white solid. LC-MS: (ES, m/z): [M+H]⁺ 567.4; ¹H-NMR: (400 MHz,DMSO-d₆, ppm): δ 9.92 (s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.49 (d, 1H),8.29 (m, 2H), 7.47-7.49 (d, 1H), 7.40 (s, 1H), 4.53 (s, 5H), 4.00 (s,2H), 3.41 (s, 1H), 2.59-2.67 (m, 4H), 2.50 (s, 3H), 2.02 (s, 2H), 1.65(d, 2H), 1.32 (d, 2H).

Example 73 Synthesis of1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of 2-(4,4-difluoropiperidin-1-yl)ethan-1-ol

Proceeding analogously as described in Example 72, Step 1, butsubstituting 4-(benzyloxy)piperidine with 4,4-difluoropiperidineprovided crude product which was used in the next step directly withoutfurther purification.

Step 2: Synthesis of1-(2-(4,4-difluoropiperidin-1-yl)ethyl)-7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 64, Step 1, butsubstituting 2-(benzyloxy)ethan-1-ol with2-(4,4-difluoropiperidin-1-yl)ethan-1-ol and methyl4-bromo-1H-pyrazole-5-carboxylate with7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided crude product. Purification by Prep-TLC (CH₂Cl₂/MeOH80:1) gave the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺587.2; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 9.91 (s, 1H), 8.73 (s, 1H),8.55 (s, 1H), 8.48 (dd, 1H), 8.29 (t, 2H), 7.46 (d, 1H), 7.42 (s, 1H),4.47-4.59 (m, 4H), 4.00 (t, 2H), 2.71 (t, 2H), 2.50-2.51 (t, 4H), 2.34(s, 3H), 1.85-1.92 (m, 4H).

Example 74 Synthesis of1-(2-(dimethylamino)ethyl)-7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 64, Step 1, butsubstituting 2-(benzyl-oxy)ethan-1-ol with 2-(dimethylamino)ethan-1-oland methyl 4-bromo-1H-pyrazole-5-carboxylate with7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one gave crude product. Purification by Prep-TLC (CH₂Cl₂/MeOH 60:1)gave the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺511.2; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 9.92 (s, 1H), 8.74 (s, 2H),8.56 (d, 1H), 8.49 (dd, 1H), 8.30 (t, 2H), 7.49 (d, 1H), 7.40 (s, 1H),4.47-4.61 (m, 4H), 4.00 (s, 2H), 2.50-2.60 (m, 2H), 2.34 (s, 3H), 2.16(s, 6H).

Example 75 Synthesis of7-[2-methyl-4-[6-(trifluoromethyl)quinazolin-2-yl]phenyl]-1-[(1H-1,2,3,4-tetrazol-5-yl)methyl]-1H,5H,6H,7H,8H-pyrazolo[3,4-f][1,4]oxazepin-8-one

Step 1: Synthesis of2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepin-1-yl)acetamide

To a stirred solution of2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepin-1-yl)aceticacid (350.00 mg, 0.704 mmol, 1.00 equiv) and NH₄Cl (150.55 mg, 2.814mmol, 4.00 equiv) in DMF (5.00 mL) were added DIEA (181.87 mg, 1.407mmol, 2.00 equiv) and HATU (668.83 mg, 1.759 mmol, 2.50 equiv) at roomtemperature under nitrogen atmosphere. The resulting mixture was stirredovernight and then diluted with water. The aqueous layer was extractedwith EtOAc and the organic layer was concentrated. The residue waspurified by reverse flash chromatography with the following conditions:Column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradientin 10 min; detector, UV 254 nm, to give the title compound (220 mg,62.98%) as a white solid.

Step 2: Synthesis of7-[2-methyl-4-[6-(trifluoromethyl)quinazolin-2-yl]phenyl]-1-[(1H-1,2,3,4-tetrazol-5-yl)methyl]-1H,5H,6H,7H,8H-pyrazolo[3,4-f][1,4]oxazepin-8-one

A solution of SiCl₄ (102.67 mg, 0.604 mmol, 3 equiv) in dioxane (2 mL)was treated with NaN₃ (39.28 mg, 0.604 mmol, 3.00 equiv) for 2 h at roomtemperature under nitrogen atmosphere, followed by the addition of2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepin-1-yl)acetamide(100 mg, 0.201 mmol, 1 equiv). The resulting mixture was stirred forovernight at 100° C. The crude product (100 mg) was purified byPrep-HPLC with the following conditions (Column: XBridge Prep OBD C18Column, 30×150 mm 5 um; Mobile Phase A: water (0.05% NH₃ in H₂O), MobilePhase B: ACN; Flow rate:60 mL/min; Gradient:26% B to 38% B in 7 min;254; 220 nm; RT:5.62 min.) to afford the title compound (46.9 mg,44.65%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 522.2; ¹H-NMR: (300MHz, DMSO-d6, ppm): δ 9.90 (s, 1H), 8.73 (s, 1H), 8.52 (s, 1H), 8.52 (d,1H), 8.28 (s, 2H), 7.43-7.45 (m, 2H), 5.97 (d, 1H), 5.79 (d, 1H), 4.55(s, 2H), 3.93-3.99 (m, 2H), 2.22 (s, 3H).

Example 76 Synthesis of2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepin-1-yl)aceticacid

Step 1: Synthesis of tert-butyl2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-H-pyrazolo[3,4-f][1,4]oxazepin-1-yl)acetate

Proceeding analogously as described in Example 64, Step 1, butsubstituting 2-(benzyloxy)ethan-1-ol with tert-butyl 2-hydroxyacetateand methyl 4-bromo-1H-pyrazole-5-carboxylate with7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided crude product. Purification by silica gel columnchromatography by eluting with PE/EtOAc (10:1) gave the title compoundas a white solid.

Step 2: Synthesis of2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepin-1-yl)aceticacid

Proceeding analogously as described in Example 71, Step 2, butsubstituting7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one with tert-butyl2-(7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepin-1-yl)acetategave crude product. Purification by reverse flash chromatography underthe following conditions: Column, C18 silica gel; mobile phase,(NH₄)₂CO₃ in water, 10% to 50% gradient in 10 min; detector, UV 254 nm,gave the title compound. LC-MS: (ES, m/z): [M+H]⁺ 498.3; ¹H-NMR: (400MHz, DMSO-d6, ppm): δ 9.90 (s, 1H), 8.72 (s, 1H), 8.53 (s, 1H), 8.47 (d,1H), 8.27 (t, 2H), 7.43 (d, 1H), 7.34 (s, 1H), 5.02-5.06 (m, 1H), 4.91(d, 1H), 4.53 (m, 2H), 3.96 (m, 2H), 2.29 (s, 3H).

Example 77 Synthesis of2-((1H-tetrazol-5-yl)methyl)-7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-2H-pyrazolo[3,4-f][1,4]oxazepin-2-yl)acetamide

Proceeding analogously as described in Example 62, Step 1, butsubstituting3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylicacid with2-(7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-2H-pyrazolo[3,4-f][1,4]oxazepin-2-yl)aceticacid and morpholine with NH₄Cl provided crude product. Purification byPrep-TLC (CH₂Cl₂/MeOH 10:1) gave the title compound as a white solid.

Step 2: Synthesis of2-((1H-tetrazol-5-yl)methyl)-7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 75, Step 2, butsubstituting of2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepin-1-yl)acetamidewith2-(7-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-2H-pyrazolo[3,4-f][1,4]oxazepin-2-yl)acetamidegave crude product which was purified by Prep-HPLC to afford the titlecompound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 522.3; ¹H-NMR: (400MHz, DMSO-d₆, ppm): δ 9.91 (s, 1H), 8.73 (s, 1H), 8.53 (s, 1H), 8.47 (d,1H), 8.29 (t, 2H), 7.57 (s, 1H), 7.44 (d, 1H), 5.44 (s, 2H), 4.52-4.44(m, 2H), 4.02-3.91 (m, 2H), 2.30 (s, 3H).

Example 78 Synthesis of2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-2H-pyrazolo[3,4-f][1,4]oxazepin-2-yl)aceticacid

To tert-butyl2-(7-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-2H-pyrazolo[3,4-f][1,4]oxazepin-2-yl)acetate(770 mg, 1.391 mmol, 1 equiv) was added hydrogen chloride in 1,4-dioxanesolution (5 ml) and the solution was stirred for 1 h at roomtemperature. The resulting mixture was concentrated under reducedpressure and the crude product was purified by Prep-HPLC under thefollowing conditions (CH₃CN: NH₄HCO₃, 40:60) to afford the titlecompound (660 mg, 95%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 498.2;¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 9.83 (s, 1H), 8.65 (s, 1H), 8.48 (s,1H), 8.43 (d, 1H), 8.25 (s, 2H), 7.56 (s, 1H), 7.41 (d, 1H), 4.71 (s,2H), 4.50-4.44 (m, 2H), 3.96-3.93 (m, 2H), 2.28 (s, 3H).

Example 79 Synthesis of3-(hydroxymethyl)-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbaldehyde

Proceeding analogously as described in Example 58, Steps 1-3, butsubstituting2-bromo-3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)-quinazolin-2-yl]phenyl]-3H,3aH,4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-onewith3-bromo-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one provided the title compound as a yellow solid.

Step 2: Synthesis of3-(hydroxymethyl)-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into an 8-mL sealed tube purged under N₂ atmosphere, were placed5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbaldehyde(100 mg, 0.222 mmol, 1 equiv), THF (2 mL), and 1-boranylpyrrolidinelithium (19.91 mg, 0.222 mmol, 1 equiv). The resulting solution wasstirred for 12 h at −78° C. and then quenched with water. The resultingsolution was extracted with ethyl acetate and the organic layer wasconcentrated. The residue was applied onto Prep-TLC and eluted withdichloromethane/methanol (15:1) to give in the title compound (40.7 mg,40.52%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 454.3; ¹H-NMR: (400MHz, DMSO-d₆, ppm): δ 2.35 (s, 3H), 3.93-3.97 (m, 1H), 4.29-4.36 (m,1H), 4.54-4.57 (m, 4H), 4.65 (s, 1H), 7.56 (d, 2H), 7.62 (s, 1H), 8.27(t, 2H), 8.40 (d, 1H), 8.52 (s, 1H), 8.73 (s, 1H), 9.91 (s, 1H).

Example 80 Synthesis of(R)—N-(1-hydroxypropan-2-yl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide

Into a 8-mL sealed tube under nitrogen atmosphere, were placed3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid (40 mg, 0.083 mmol, 1 equiv), (2R)-2-aminopropan-1-ol (9.36 mg,0.125 mmol, 1.50 equiv), DMF (1.2 mL), EDCI (19.11 mg, 0.100 mmol, 1.2equiv), and HOBT (13.47 mg, 0.100 mmol, 1.2 equiv). The resultingsolution was stirred for 12 h at room temperature and then quenched withwater. The resulting solution was extracted with ethyl acetate and theorganic layers combined and concentrated under vacuum. The residue waspurified by Prep-TLC (CH₂Cl₂/MeOH 20:1) to afford the title compound(4.32 mg, 9.65%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 539.3;¹H-NMR: (400 MHz, DMSO, ppm): δ 9.91 (s, 1H), 8.73 (s, 1H), 8.56 (s,1H), 8.50 (d, 1H), 8.29 (s, 2H), 7.73 (d, 1H), 7.57 (d, 1H), 4.80 (t,1H), 4.59 (d, 2H), 4.33 (s, 1H), 3.98 (s, 2H), 3.43-3.33 (m, 2H), 2.36(s, 3H), 1.13 (d, 3H).

Example 81 Synthesis of(S)-3-((1-hydroxypropan-2-yl)amino)-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 8-mL sealed tube under nitrogen atmosphere, were placed3-bromo-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (100 mg, 0.199 mmol, 1 equiv), (2S)-2-aminopropan-1-ol (149.54mg, 1.991 mmol, 10 equiv), picolinic acid (244.88 mg, 1.991 mmol, 10equiv), K₂CO₃ (137.57 mg, 0.995 mmol, 5 equiv), CuSO₄ (317.76 mg, 1.991mmol, 10 equiv), and DMF (2 mL). The resulting solution was stirred for12 h at 110° C. and then quenched with water. The resulting solution wasextracted with ethyl acetate and the organic layer was concentrated. Theresidue was applied onto Prep-TLC and eluted withdichloromethane/methanol (20:1) to give the title compound (36.1 mg,36.52%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 497.4; ¹H-NMR: (400MHz, DMSO-d₆, ppm): δ 1.12 (s, 3H), 2.33 (s, 3H), 3.39 (s, 2H),3.86-3.88 (m, 1H), 4.26 (s, 1H), 4.40 (s, 2H), 4.76 (s, 1H), 4.89 (d,1H), 7.23 (s, 1H), 7.52 (d, 1H), 8.25 (t, 2H), 8.46 (d, 1H), 8.52 (s,1H), 8.70 (s, 1H), 9.88 (s, 1H).

Example 82 Synthesis of3-(hydroxymethyl)-1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-pyrido-[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Step 1: Synthesis of3-bromo-1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]-pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

To a stirred solution of1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (2.00 g, 4.401 mmol, 1.00 equiv) in EtOH (40.00 mL) and H₂O(8.00 mL) were added NaOAc (0.72 g, 8.803 mmol, 2 equiv) and Br₂ (1.41g, 8.823 mmol, 2.00 equiv) at room temperature. The resulting mixturewas stirred for overnight at 60° C. and then diluted with water. Theresulting mixture was concentrated under vacuum and the aqueous layerwas extracted with EtOAc. The organic layer was concentrated undervacuum and the residue was purified by silica gel column chromatographyby eluting with PE/EtOAc (5:1) to the title compound (1.2 g, 51.12%) asa white solid.

Step 2: Synthesis of1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepine-3-carbaldehyde

Proceeding analogously as described in Example 58, Steps 1-3, butsubstituting2-bromo-3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)-quinazolin-2-yl]phenyl]-3H,3aH,4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-onewith3-bromo-1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided the title compound as a white solid.

Step 3: Synthesis of3-(hydroxymethyl)-1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-pyrido-[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

To a stirred solution of1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepine-3-carbaldehyde(100 mg, 0.207 mmol, 1 equiv) in THF (4 mL) was added NaBH₃CN (39.08 mg,0.622 mmol, 3.00 equiv) at room temperature. The resulting mixture wasstirred for 2 days at room temperature. The reaction was quenched withsat. NH₄Cl (aq.) at room temperature. The aqueous layer was extractedwith EtOAc (4×510 mL). The residue was purified by Prep-TLC (CH₂Cl₂/MeOH40:1) to afford the title compound (21.9 mg, 21.81%) as a white solid.LC-MS: (ES, m/z): [M+H]⁺ 485.3; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 9.95(s, 1H), 8.81 (d, 1H), 8.54 (s, 1H), 8.44-8.49 (m, 2H), 7.49 (d, 1H),4.97 (t, 1H), 4.44-4.60 (m, 2H), 4.36 (d, 2H), 3.97-3.99 (m, 5H), 2.32(s, 3H).

Example 83 Synthesis of3-(1-hydroxyethyl)-1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Into a 25-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepine-3-carbaldehyde(50 mg, 0.11 mmol, 1.00 equiv), oxolane (0.50 mg), andchloro-(methyl)magnesium (0.33 mL, 0.30 mmol, 3.00 equiv). The resultingsolution was stirred for 3 h at room temperature and then quenched withwater/ice. The resulting solution was extracted with ethyl acetate andorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (1/1) to give the titlecompound (21.0 mg) as a white solid. LC-MS (ES, m/z): [M+H]⁺ 499.2;¹H-NMR (300 MHz, DMSO-d₆, ppm): δ 9.95 (s, 1H), 8.83 (d, 1H), 8.56 (s,1H), 8.45-8.49 (m, 2H), 7.49 (d, 1H), 4.88-5.01 (m, 1H), 4.71-4.82 (m,1H), 4.43-4.62 (m, 2H), 3.95 (s, 5H), 2.31 (s, 3H), 1.43 (d, 3H).

Example 84 Synthesis of3-(2-hydroxypropan-2-yl)-1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding analogously as described in Example 59, Step 1, butsubstituting ethyl3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylatewith ethyl1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepine-3-carboxylateprovided crude product. Purification by prep-TLC (PE/EtOAc 60:1) gavethe title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 513.3;¹H-NMR: (300 MHz, DMSO-d6, ppm): δ 9.95 (s, 1H), 8.81 (d, 1H), 8.54 (s,1H), 8.45-8.50 (m, 2H), 7.49 (d, 1H), 4.73 (s, 1H), 4.52 (t, 2H), 3.95(t, 5H), 2.32 (s, 3H), 1.48 (s, 6H).

Example 85 Synthesis of3-((dimethylamino)methyl)-1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido-[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one

Proceeding as described in Example 63 but substituting3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehydewith1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepine-3-carbaldehydegave crude product. Purification by Prep-TLC (CH₂Cl₂/MeOH 40:1) gave thetitle compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 512.2; ¹H-NMR:(300 MHz, DMSO-d₆, ppm): δ 9.95 (s, 1H), 8.81 (d, 1H), 8.54-8.54 (d,1H), 8.44-8.49 (m, 2H), 7.48 (d, 1H), 4.45-4.56 (m, 2H), 3.97 (s, 5H),3.28-3.33 (t, 2H), 2.32 (s, 3H), 2.14 (s, 6H).

Example 86 Synthesis of ethyl1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-8-oxo-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepine-3-carboxylate

Proceeding as described in Example 56, Step 2, but substituting2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one with3-bromo-1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one provided crude product. Purification by Prep-TLC (CH₂Cl₂/MeOH60:1) and a second Prep-HPLC under the following conditions (Column:XBridge Prep OBD C18 Column, 19*250 mm, 5 um; Mobile Phase A: water(0.05% NH₃—H₂O), Mobile Phase B: ACN; Flow rate: 20 mL/min; Gradient: 49B to 49 B in 11.5 min; 254; 220 nm; RT:10.83 min) gave the titlecompound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 527.2; ¹H-NMR: (300MHz, DMSO-d6, ppm): δ 9.95 (s, 1H), 8.81 (d, 1H), 8.45-8.55 (m, 3H),7.49 (d, 1H), 4.55-4.63 (m, 2H), 4.23-4.30 (m, 2H), 4.05 (d, 5H), 2.33(s, 3H), 1.21-1.30 (m, 3H).

Example 87 Synthesis of2-(hydroxymethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 56, Step 1, butsubstituting3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one with3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one gave crude product. Purification by silica gel columnchromatography (PE/EA 5:1) gave the title compound as a light-yellowsolid.

Step 2: Synthesis of2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 8-mL sealed tube under N₂ atmosphere, were placed2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (300 mg, 0.581 mmol, 1 equiv), Bu₃SnCH₃OTBS (380.00 mg, 0.872mmol, 1.50 equiv), toluene (3.5 mL, 0.038 mmol, 0.07 equiv), andPd(PPh₃)₄ (134.28 mg, 0.116 mmol, 0.2 equiv). The resulting solution wasstirred for 12 h at 110° C. in an oil bath. The reaction mixture wasthen quenched with water and the resulting solution was extracted withethyl acetate. The organic layers were combined and concentrated underreduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 1:1) toafford the title compound (130 mg, 38.46%) as a white solid.

Step 3: Synthesis of2-(hydroxymethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into an 8-mL sealed tube, were placed2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (130 mg, 0.223 mmol, 1 equiv), THF (2.5 mL), and TBAF (175.29mg, 0.670 mmol, 3.00 equiv). The resulting solution was stirred for 4 hat room temperature and then quenched with NH₄Cl. The resulting solutionwas extracted with ethyl acetate and the organic layers were combinedand concentrated under vacuum. The residue was purified by Prep-TLC(hexane/EtOAc 1:1) to afford the title compound (51 mg, 48.82%) as awhite solid. LC-MS: (ES, m/z): [M+H]⁺ 468.2; ¹H-NMR: (400 MHz; d₆-DMSO,ppm): δ 8.81 (d, 1H), 8.71 (d, 1H), 8.63 (d, 1H), 8.34 (s, 1H), 8.27(dd, 2H), 7.57 (d, 1H), 5.00 (t, 1H), 4.48 (dd, 4H), 4.30 (dt, 1H),3.92-3.98 (m, 1H), 2.35 (s, 3H), 2.28 (s, 3H).

Example 88 Synthesis of2-(hydroxymethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-pyrido-[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 56, Step 1, butsubstituting3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one with3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one provided crude product. Purification by prep-TLC (CH₂Cl₂/MeOH60:1) provided the title compound as a white solid.

Step 2: Synthesis of2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 87, Step 2, butsubstituting2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo-[1,5-a]pyrazin-4(5H)-one with2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one provided crude product. Purification by Prep-TLC (CH₂Cl₂/MeOH100:1) gave the title compound as a white solid.

Step 3: Synthesis of2-(hydroxymethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-pyrido-[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 87, Step 3, butsubstituting2-(((tert-butyldimethylsilyl)oxy)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one with2-(((tert-butyldimethyl-silyl)oxy)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one gave the title compound as a crude product. Purification byPrep-TLC (EtOAc) gave the title compound as a white solid. LC-MS: (ES,m/z): [M+H]⁺ 469.2; ¹H-NMR: (400 MHz, CDCl₃, ppm): δ 9.81 (s, 1H), 8.65(s, 1H), 8.57-8.60 (m, 2H), 8.14 (d, 1H), 7.40 (d, 1H), 4.74 (s, 2H),4.53 (t, 2H), 4.22-4.29 (m, 1H), 3.91-3.97 (m, 1H), 2.40-2.43 (d, 6H).

Example 89 Synthesis of2-(2-hydroxyethoxy)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 5-mL sealed tube under N₂ atmosphere, were placed2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (200.00 mg, 0.387 mmol, 1.00 equiv), ethane-1,2-diol (3.00 mL),t-BuOLi (93.03 mg, 1.162 mmol, 3.00 equiv), and Cu(OAC)₂ (14.07 mg,0.077 mmol, 0.20 equiv). The final reaction mixture was irradiated withmicrowave radiation for 2 h at 150° C. and then quenched with water. Theresulting solution was extracted with ethyl acetate and the organiclayers were combined and concentrated. The residue was applied onto aPrep TLC with ethyl acetate/petroleum ether (1:1) to give the titlecompound (41.8 mg, 21.69%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺498.3; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 2.11 (s, 3H), 2.34 (s, 3H),3.70-3.72 (m, 2H), 3.73-3.75 (m, 1H), 4.18-4.35 (m, 5H), 4.83-4.86 (m,1H), 7.56 (d, 1H), 8.29 (s, 2H), 8.50 (d, 1H), 8.56 (s, 1H), 8.74 (s,1H), 9.92 (s, 1H).

Example 90 Synthesis of7-((benzyloxy)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of1-(1,3-bis(benzyloxy)propan-2-yl)-4-methyl-1H-pyrazole-5-carboxylic acid

Proceeding analogously as described in Example 64, Steps 1 and 2, butsubstituting methyl 4-bromo-1H-pyrazole-5-carboxylate with ethyl4-methyl-1H-pyrazole-5-carboxylate and 2-(benzyloxy)ethan-1-ol with1,3-bis(benzyloxy)propan-2-ol gave crude product. Purification by silicagel column with ethyl acetate/petroleum ether (1:20) gave the titlecompound as a light brown liquid.

Step 2: Synthesis of1-(1,3-bis(benzyloxy)propan-2-yl)-4-methyl-1H-pyrazole-5-carbonylchloride

Proceeding analogously as described in Example 1, Step 7, butsubstituting 4-(2-(benzyloxy)ethoxy)-1-methyl-1H-pyrazole-5-carboxylicacid with1-(1,3-bis(benzyloxy)propan-2-yl)-4-methyl-1H-pyrazole-5-carboxylic acidgave the title compound as a brown solid.

Step 3: Synthesis of1-(1,3-bis(benzyloxy)propan-2-yl)-4-methyl-N-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-1H-pyrazole-5-carboxamide

Proceeding analogously as described in Example 1, Step 8, butsubstituting 4-(2-(benzyloxy)ethoxy)-1-methyl-1H-pyrazole-5-carbonylchloride with1-(1,3-bis(benzyloxy)propan-2-yl)-4-methyl-1H-pyrazole-5-carbonylchloride and 4-bromo-2-methylaniline with2-methyl-4-[6-(trifluoromethyl)quinazolin-2-yl]aniline gave crudeproduct. The crude product was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (1:2) to give the titlecompound as a brown solid.

Step 4: Synthesis of7-((benzyloxy)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 1, Steps 9-11, butsubstituting4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamidewith(1,3-bis(benzyloxy)propan-2-yl)-4-methyl-N-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-1H-pyrazole-5-carboxamidegave crude product. The crude product was applied onto a Prep TLC andeluted with ethyl acetate/petroleum ether (1:1) to give the titlecompound as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 558.3; ¹H-NMR: (400MHz, DMSO-d₆, ppm): δ 2.19-2.34 (m, 6H), 3.79-3.89 (m, 2H), 3.95-4.04(m, 1H), 4.09-4024 (m, 1H), 4.45-4.63 (m, 3H), 4.82-4.95 (m, 1H),7.20-7.43 (m, 5H), 7.54 (s, 1H) 7.58 (d, 1H), 8.28 (t, 2H), 8.42-8.60(m, 2H), 8.55 (s, 1H), 8.74 (s, 1H), 9.91 (s, 1H).

Example 91 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-2-((2-methylmorpholino)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61 but substitutingmorpholine with 2-methylmorpholine provided crude product. Purificationby Prep-TLC (CH₂Cl₂/MeOH 40:1), followed by reverse flash chromatography[column, C18 silica gel; mobile phase, MeOH in water, 10% to 50%gradient in 10 min; detector, UV 254 nm] gave the title compound as awhite solid. LC-MS: (ES, m/z): [M+H]⁺ 551.3; ¹H-NMR: (300 MHz, DMSO-d6,ppm): δ 9.90 (s, 1H), 8.71 (s, 1H), 8.53 (s, 1H), 8.48 (d, 1H), 8.27 (m,2H), 7.54 (d, 1H), 4.46 (d, 2H), 4.25-4.32 (m, 1H), 3.84-3.94 (m, 1H),3.67-3.77 (m, 1H), 3.45 (s, 4H), 2.57-2.75 (m, 2H), 2.33 (s, 3H), 2.25(s, 3H), 1.97-2.11 (m, 1H), 1.68-1.81 (m, 1H), 1.02 (d, 3H).

Example 92 Synthesis of2-(1-hydroxyethyl)-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of diethyl1-(2-(benzyloxy)ethyl)-1H-pyrazole-3,5-dicarboxylate

Proceeding analogously as described in Example 64, Steps 1 and 2, butsubstituting methyl 4-bromo-1H-pyrazole-5-carboxylate with diethyl1H-pyrazole-3,5-dicarboxylate provided the title compound as a yellowsolid.

Step 2: Synthesis of5-(4-bromo-2-methylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicacid

Proceeding analogously as described in Example 1, Steps 7-11, butsubstituting 4-(2-(benzyloxy)ethoxy)-1-methyl-1H-pyrazole-5-carboxylicacid with1-(2-(benzyloxy)ethyl)-3-(methoxycarbonyl)-1H-pyrazole-5-carboxylic acidprovided the title compound as a yellow solid.

Step 3: Synthesis of5-(4-bromo-2-methylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbonylchloride

Proceeding analogously as described in Example 1, Step 7, butsubstituting 4-(2-(benzyloxy)ethoxy)-1-methyl-1H-pyrazole-5-carboxylicacid with5-(4-bromo-2-methylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylicgave the title compound as a yellow liquid.

Step 4: Synthesis of5-(4-bromo-2-methylphenyl)-N-methoxy-N-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced5-(4-bromo-2-methylphenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbonylchloride (2.50 g, 6.782 mmol, 1.00 equiv), Et₃N (1.03 g, 10.173 mmol,1.50 equiv), DCM (50 ml), and methoxy(methyl)amine (0.50 g, 8.138 mmol,1.20 equiv). The resulting solution was stirred for 1 h at 0° C. andthen concentrated. The residue was applied onto a silica gel column andeluted with dichloromethane/methanol (80:1) to give the title compound(1.3 g, 48.74%) as a yellow solid.

Step 5: Synthesis ofN-methoxy-N-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide

Proceeding analogously as described in Example 1, Step 12, butsubstituting7-(4-bromo-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f]-[1,4]oxazepin-8(5H)-one with5-(4-bromo-2-methylphenyl)-N-methoxy-N-methyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamidegave crude product. Purification by silica gel column with ethylacetate/petroleum ether (1:1) gave the title compound as a yellowliquid.

Step 6: Synthesis ofN-methoxy-N-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide

Proceeding analogously as described in Example 49, Step 2, butsubstituting1-methyl-7-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-f][1,4]oxazepaneN-methoxy-N-methyl-5-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamideand K₃PO₄ with K₂CO₃ gave crude product. Purification by silica gelcolumn with ethyl acetate/petroleum ether (2:1) as eluent gave the titlecompound as a yellow solid.

Step 7: Synthesis of2-acetyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 58, Step 4, butsubstituting3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehydewithN-methoxy-N-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamidegave crude product. Purification by Prep-TLC withdichloromethane/methanol (30:1) gave the title compound as a yellowsolid.

Step 8: Synthesis of2-(1-hydroxyethyl)-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 79, Step 2, butsubstituting5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbaldehydewith2-acetyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one gave crude product. Purification by Prep-TLC withdichloromethane/methanol (40:1) gave the title compound as a whitesolid. LC-MS: (ES, m/z): [M+H]⁺ 468.3; ¹H-NMR: (300 MHz, DMSO-d₆, ppm):δ 1.40 (d, 3H), 2.64 (s, 3H), 3.97-3.98 (m, 1H), 4.25-4.35 (m, 1H),4.51-4.55 (m, 2H), 4.76-4.78 (m, 1H), 5.20 (d, 1H), 6.76 (s, 1H), 7.57(d, 1H), 8.28 (t, 2H), 8.50 (d, 1H), 8.55 (s, 1H), 8.73 (s, 1H), 9.91(s, 1H).

Example 93 Synthesis of8-methyl-2-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3,4-dihydro-2H-pyrazolo[1,5-e][1,2,5]thiadiazine1,1-dioxide

Step 1: Synthesis of 5-iodo-4-methyl-1H-pyrazole

Into a 250-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced 4-methyl-1H-pyrazole (5.00 g, 60.897 mmol, 1.00 equiv), DMF(100.00 mL), and NIS (14.39 g, 63.942 mmol, 1.05 equiv). The resultingsolution was stirred for 1 h at 25° C. and then quenched with water. Theresulting solution was extracted with ethyl acetate and the organiclayer was separated and concentrated in vacuum. The residue was by Flashchromatography to give the title compound (4 g, 31.58%) as a whitesolid.

Step 2: Synthesis of 5-(benzylthio)-4-methyl-1H-pyrazole

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced 5-iodo-4-methyl-1H-pyrazole (2.00 g, 9.615 mmol, 1.00 equiv),CuSO₄ (3.07 g, 19.231 mmol, 2.00 equiv), K₂CO₃ (2.66 g, 19.231 mmol,2.00 equiv), DMF (50.00 mL), (2.37 g, 19.231 mmol, 2.00 equiv), andpicolinic acid (5.96 g, 48.076 mmol, 5.00 equiv). The resulting solutionwas stirred for 12 h at 110° C. The reaction was then quenched by theaddition of water. The resulting solution was extracted with ethylacetate and the organic layer was separated and concentrated. Theresidue was applied onto a silica gel column withdichloro-methane/methanol (50:1) to give (2.5 g, 127.27%) of the titlecompound as a yellow solid.

Step 3: Synthesis of1-(2-(benzyloxy)ethyl)-5-(benzylthio)-4-methyl-1H-pyrazole

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced 5-(benzylthio)-4-methyl-1H-pyrazole (2.30 g, 11.259 mmol, 1.00equiv), 2-(benzyloxy)ethan-1-ol (3.43 g, 22.517 mmol, 2.00 equiv), DIAD(4.55 g, 22.517 mmol, 2.00 equiv), THF (50.00 mL), and PPh₃ (5.91 g,22.517 mmol, 2.00 equiv). The resulting solution was stirred for 1 h at0° C. and then concentrated. The residue was applied onto a silica gelcolumn and eluted with ethyl acetate/petroleum ether (1:50) to give thetitle compound (1.2 g, 31.49%) as a yellow liquid.

Step 4: Synthesis of1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-sulfonyl chloride

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced 1-(2-(benzyloxy)ethyl)-5-(benzylthio)-4-methyl-1H-pyrazole (1.20g, 3.545 mmol, 1.00 equiv), MeCN (40.00 mL), AcOH (0.50 mL), H₂O (1.00mL), and DCDMH (1.39 g, 7.091 mmol, 2.00 equiv). The resulting solutionwas stirred for 12 h at 25° C. and then concentrated to give the titlecompound (2.5 g, 116.88%) as a yellow liquid.

Step 5: Synthesis of1-(2-(benzyloxy)ethyl)-4-methyl-N-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-1H-pyrazole-5-sulfonamide

Into a 100-mL 3-necked round-bottom flask under N₂ atmosphere, wereplaced 1-(2-(benzyloxy)ethyl)-4-methyl-1H-pyrazole-5-sulfonyl chloride(2.50 g, 7.942 mmol, 1.00 equiv),2-methyl-4-[6-(trifluoromethyl)quinazolin-2-yl]aniline (3.61 g, 11.913mmol, 1.50 equiv), and pyridine (50.00 mL). The resulting solution wasstirred for 12 h at 25° C. and then concentrated. The residue waspurified by Flash chromatography to give (200 mg, 4.33%) of the titlecompound as a yellow solid.

Step 6: Synthesis of1-(2-hydroxyethyl)-4-methyl-N-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-1H-pyrazole-5-sulfonamide

Into an 8-mL sealed tube purged and maintained under nitrogenatmosphere, were placed1-(2-(benzyloxy)ethyl)-4-methyl-N-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-1H-pyrazole-5-sulfonamide(190.00 mg, 0.327 mmol, 1.00 equiv), DCM (5.00 mL), and BCl₃ (1M) (0.33mL). The resulting solution was stirred for 1 h at 0° C. and thenquenched with NaHCO₃. The resulting solution was extracted with ethylacetate and the organic layer was separated and concentrated. Theresidue was applied onto Prep-TLC and eluted with withdichloromethane/methanol (20:1) to give the title compound (100 mg,62.28%) as a yellow solid.

Step 7: Synthesis of8-methyl-2-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-3,4-dihydro-2H-pyrazolo[1,5-e][1,2,5]thiadiazine1,1-dioxide

Into a 20-mL sealed tube under nitrogen atmosphere, were placed1-(2-hydroxyethyl)-4-methyl-N-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-1H-pyrazole-5-sulfonamide(90.00 mg, 0.183 mmol, 1.00 equiv), THF (9.00 mL), PPh₃ (96.06 mg, 0.366mmol, 2.00 equiv), and DIAD (74.06 mg, 0.366 mmol, 2.00 equiv). Theresulting solution was stirred for 1 h at 0° C. and then concentrated.The residue was applied onto Prep-TLC and eluted withdichloromethane/methanol (30:1) to give the title compound (44.2 mg,50.98%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 474.3; ¹H-NMR: (400MHz, DMSO-d₆, ppm): δ 2.25 (s, 3H), 2.66 (s, 3H), 4.18-4.21 (m, 1H),4.35-4.50 (m, 3H), 7.24 (d, 1H), 7.64 (s, 1H), 8.27 (t, 1H), 8.42 (d,1H), 8.59 (s, 1H), 8.72 (s, 1H), 9.90 (s, 1H).

Example 94 Synthesis of5-(5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazolidine-2,4-dione

Step 1: Synthesis of5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbaldehyde

Proceeding analogously as described in Example 58, Steps 1-3, butsubstituting2-bromo-3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)-quinazolin-2-yl]phenyl]-3H,3aH,4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-onewith3-bromo-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one gave crude product. Purification by silica gel column withethyl acetate/petroleum ether (1:5) gave the title compound as a yellowsolid.

Step 2: Synthesis of5-(5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)imidazolidine-2,4-dione

Into a 8-mL sealed tube under N₂ atmosphere, were placed5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carbaldehyde(100 mg, 0.229 mmol, 1 equiv), KCN (29.78 mg, 0.457 mmol, 2 equiv),(NH₄)₂CO₃ (131.81 mg, 1.372 mmol, 6 equiv), and EtOH (50%) (2 mL). Theresulting solution was stirred for 6 h at 60° C. and then quenched withNaHCO₃. The resulting solution was extracted with ethyl acetate andorganic layer was concentrated. The residue was applied onto Prep-TLCwith chloroform/methanol (10:1) to give the title compound (16.9 mg,14.18%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 522.3; ¹H-NMR: (400MHz, DMSO-d₆, ppm): δ 2.34 (d, 3H), 3.90-4.10 (m, 1H), 4.20-4.40 (m,1H), 4.53-4.68 (m, 2H), 5.52 (d, 1H), 7.58 (t, 1H), 7.68 (d, 1H), 8.09(s, 1H), 8.28 (t, 2H), 8.50 (d, 1H), 8.56 (s, 1H), 8.73 (s, TH), 9.91(s, TH), 10.71 (s, TH).

Example 95 Synthesis of(R)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-2-((2-methylmorpholino)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61 but substitutingmorpholine with (2R)-2-methylmorpholine gave crude product. Purificationby Prep-TLC (CH₂Cl₂/MeOH 40:1) gave the title compound as a white solid.LC-MS: (ES, m/z): [M+H]⁺ 551.3; ¹H-NMR: (400 MHz, DMSO-D₆, ppm): δ 9.91(s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.50 (d, 1H), 8.29 (t, 2H),7.54-7.56 (d, 1H), 4.50 (bs, 2H), 4.26-4.33 (m, 1H), 3.90-3.93 (m, 1H),3.74 (bs, 1H), 3.48 (bs, 4H), 2.67-2.77 (m, 2H), 2.35 (s, 3H), 2.27 (s,3H), 1.99-2.07 (bs, 1H), 1.76-1.82 (bs, 1H), 1.05 (d, 3H).

Example 96 Synthesis of(S)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-2-((2-methylmorpholino)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61 but substitutingmorpholine with (2S)-2-methylmorpholine gave crude product. Purificationby prep-tlc (CH₂Cl₂/MeOH 30:1) gave the title compound as a white solid.LC-MS: (ES, m/z): [M+H]⁺ 551.4; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 9.90(s, 1H), 8.72 (s, 1H), 8.55 (s, 1H), 8.48 (d, 1H), 8.50 (m, 2H), 8.28(s, 2H), 7.54 (d, 1H), 4.49 (t, 2H), 4.28-4.32 (m, 1H), 3.89-3.93 (m,1H), 3.74 (d, 1H), 3.46 (s, 4H), 2.68 (d, 2H), 2.35 (s, 3H), 2.26 (s,3H), 2.06 (t, 1H), 1.76 (t, 1H), 1.04 (d, 3H).

Example 97 Synthesis of(3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyldihydrogen phosphate

Step 1: Synthesis of2-(chloromethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred solution/mixture of2-(hydroxymethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (170.00 mg, 0.364 mmol, 1.00 equiv) and TEA (110.40 mg, 1.091mmol, 3 eq) in DCM (5 mL) and in a 8 mL vial, MsCl (124.98 mg, 1.091mmol, 3.00 equiv) was added dropwise at degrees C. The resulting mixturewas stirred overnight at RT under nitrogen atmosphere. The resultingmixture was diluted with water (20 mL) and extracted with EtOAc (4×20mL). The EA phase was concentrated under vacuum. The residue waspurified by Prep-TLC (CH₂Cl₂:MeOH=50:1) gave the title compound (50 mg,96.2%) as a white solid.

Step 2: Synthesis of di-tert-butyl((3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyl)phosphate

To a stirred solution of2-(chloromethyl)-3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)quinazolin-2-yl]phenyl]-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(220.00 mg, 0.453 mmol, 1.00 equiv) in DMF (8.00 mL) in a 20 mL vial,di-tert-butyl potassium phosphate (1124.22 mg, 4.528 mmol, 10.00 equiv)at room temperature. The resulting mixture was stirred for 3 days at 50degrees C. under nitrogen atmosphere. The resulting mixture was dilutedwith water (30 mL). The aqueous layer was extracted with EtOAc (4×30mL). The resulting mixture was concentrated under vacuum. The residuewas purified by Prep-TLC (CH₂Cl₂:MeOH=120:1) to afford di-tert-butyl(3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)quinazolin-2-yl]phenyl]-4-oxo-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl)methylphosphate (150 mg, 50.22%) as a white solid.

Step 3: Synthesis of(3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)methyldihydrogen phosphate

To a stirred solution of di-tert-butyl(3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)quinazolin-2-yl]phenyl]-4-oxo-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl)methylphosphate (140.00 mg, 0.212 mmol, 1 equiv) in DCM (4.00 mL) in an 8 mLvial, TFA (2.00 mL) was added at 0° C. The resulting mixture was stirredfor 1 h at room temperature and then concentrated under reducedpressure. The resulting mixture was diluted with CH₂Cl₂ (5 mL) and thenconcentrated under reduced pressure. The resulting mixture was dilutedwith DMF (4 mL) and then concentrated under reduced pressure. Theresidue was purified by reverse flash chromatography with the followingconditions (C18 silica gel; mobile phase, MeOH in water, 10% to 50%gradient in 10 min; detector, UV 254 nm) gave the title compound (31.1mg) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 548.3; ¹H-NMR: (400 MHz,DMSO-d₆, ppm): δ 9.90 (s, 1H), 8.72 (s, 1H), 8.55 (s, 2H), 8.48 (d, 1H),8.28 (t, 1H), 7.55 (d, 1H), 4.85 (d, 2H), 4.52 (t, 2H), 4.27-4.34 (m,1H), 3.91-3.94 (m, 1H), 2.34 (s, 3H), 2.27 (s, 3H).

Example 98 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-2-((4-oxopiperidin-1-yl)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substitutingmorpholine with piperidin-4-one hydrochloride gave crude product.Purification by reverse flash chromatography (conditions: column, c18silica gel; mobile phase, meoh in water, 10% to 50% gradient in 10 min;detector, uv 254 nm) gave the title compound as a white solid. LC-MS:(ES, m/z): [M+H]⁺ 549.4; ¹H-NMR: (400 MHz, DMSO-d6, ppm): δ 9.90 (s,1H), 8.72 (s, 1H), 8.49-8.55 (m, 2H), 8.28 (s, 2H), 7.55 (d, 1H), 4.49(s, 2H), 4.29 (s, 1H), 3.92 (s, 1H), 3.62 (s, 2H), 2.72 (s, 4H),2.30-2.50 (m, 10H).

Example 99 Synthesis of2-((4-fluoropiperidin-1-yl)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substitutingmorpholine with 4-fluoropiperidine gave crude product. Purification byPrep-TLC (CH₂Cl₂/MeOH 40:1) gave the title compound as a white solid.LC-MS: [M+H]⁺ 553.4; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 9.91 (s, 1H),8.74 (s, 1H), 8.55 (s, 1H), 8.49 (d, 1H), 8.29 (m, 2H), 7.56 (d, 1H),4.47-4.51 (m, 3H), 4.28-4.32 (m, 1H), 3.89-3.93 (m, 1H), 3.48 (bs, 2H),2.50-2.51 (s, 2H), 2.26-2.34 (m, 8H), 1.60-1.88 (m, 4H).

Example 100 Synthesis of2-((4-hydroxypiperidin-1-yl)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substitutingmorpholine with 4-hydroxypiperidine gave crude product. The crudeproduct was purified by reverse flash chromatography (Conditions:column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradientin 10 min; detector, UV 254 nm) to give the title compound as a whitesolid. LC-MS: (ES, m/z): [M+H]⁺ 551.4; ¹H-NMR: (400 MHz, DMSO-d₆, ppm):δ 9.91 (s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.48 (d, 1H) (d, 1H), 8.29(t, 2H), 7.55 (d, 1H), 4.55 (s, 1H), 4.47-4.50 (m, 2H), 4.26-4.33 (m,1H), 3.90-3.93 (m, 1H), 3.43 (s, 3H), 2.64-2.72 (m, 2H), 2.35 (s, 3H),2.25 (s, 3H), 2.05 (s, 2H), 1.71 (d, 2H), 1.36 (d, 2H).

Example 101 Synthesis of2-((1,1-dioxidothiomorpholino)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoro-methyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 8 mL vial were added3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)quinazolin-2-yl]phenyl]-4-oxo-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazine-2-carbaldehyde(50.00 mg, 0.107 mmol, 1.00 equiv) and THF (1.00 mL) at roomtemperature. Thiomorpholine-1,1-dione (72.61 mg, 0.537 mmol, 5.00 equiv)was added at room temperature and the resulting mixture was stirredovernight. To the above mixture was added acetic acid (0.01 mL) at roomtemperature and NaBH₃CN (13.50 mg, 0.215 mmol, 2 equiv) at 0° C. Theresidue was purified by Prep-TLC (CH₂Cl₂/MeOH 40:1) to afford the titlecompound (20.7 mg, 16.48%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺585.4; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 9.92 (s, 1H), 8.74 (s, 1H),8.55 (s, 1H), 8.49 (d, 1H), 8.29 (t, 2H), 7.56 (d, 1H), 4.49-4.53 (m,3H), 4.28-4.32 (m, 1H), 3.89-3.93 (m, 2H), 3.10-3.12 (m, 4H), 2.93 (s,4H), 2.36 (m, 3H), 2.29 (m, 3H), 2.08 (m, 1H)

Example 102 Synthesis of2-((2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substitutingmorpholine with 2-oxa-7-azaspiro[3.5]nonane gave crude product.Purification by reverse flash chromatography (Conditions: column, C18silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min;detector, UV 254 nm) gave the title compound as a white solid. LC-MS:(ES, m/z): [M+H]⁺ 577.4; ¹H-NMR: (300 MHz, CDCl₃, ppm): δ 9.59 (s, 1H),8.65 (s, 1H), 8.58 (d, 1H), 8.29 (s, 1H), 8.23 (d, 1H), 8.11 (d, 1H),7.41 (d, 1H), 4.54 (t, 2H), 4.44 (s, 4H), 4.26 (m, 1H), 3.55 (s, 2H),2.45 (s, 9H), 1.95 (s, 4H), 1.65 (s, 2H)

Example 103 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-2-((4-methyl-piperazin-1-yl)methyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substitutingmorpholine with 1-methylpiperazine gave crude product. Purification byPrep-TLC (CH₂Cl₂/MeOH 40:1) gave the title compound as a white solid.LC-MS:(ES, m/z): [M+H]⁺ 550; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 9.91 (s,1H), 8.73 (s, 1H), 8.55 (s, 1H), 8.50 (d, 1H), 8.28 (t, 2H), 7.56 (d,1H), 4.48 (t, 2H), 4.28-4.32 (m, 1H), 3.88-3.92 (m, 1H), 3.45 (s, 2H),3.32-3.34 (s, 1H), 2.34 (s, 7H), 2.30 (s, 6H), 2.25 (s, 3H).

Example 104 Synthesis of3-methyl-2-((4-methyl-3-oxopiperazin-1-yl)methyl)-5-(2-methyl-4-(6-(trifluoro-methyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substitutingmorpholine with 1-methylpiperazin-2-one gave crude product. Purificationby Prep TLC (CH₂Cl₂/MeOH 40:1) gave the title compound as a white solid.LC-MS: (ES, m/z): [M+H]⁺ 564.4; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 9.91(s, 1H), 8.74 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.50 (d, 1H), 8.29(t, 2H), 7.56 (d, 1H), 4.50-4.51 (m, 2H), 4.27-4.36 (m, 1H), 3.90-3.94(m, 1H), 3.58-3.62 (m, 2H), 3.28-3.35 (d, 2H), 3.05 (s, 2H), 2.86 (s,3H), 2.82 (s, 1H), 2.50 (s, 1H), 2.35 (s, 3H), 2.27 (s, 3H)

Example 105 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-2-(morpholinomethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde

Proceeding analogously as described in Example 58, Steps 1 to 3, butsubstituting2-bromo-3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)-quinazolin-2-yl]phenyl]-3H,3aH,4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-onewith2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one provided crude product. Purification by Prep-TLC (CH₂Cl₂/MeOH60:1) gave the title compound as a solid.

Step 2: Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-2-(morpholinomethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substituting3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehydewith3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehydeprovided crude product. Purification by reverse flash chromatography(Conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to50% gradient in 10 min; detector, UV 254 nm) provided the title compoundas a white solid. LC-MS: (ES, m/z): [M+H]⁺ 538.4; ¹H-NMR: (400 MHz,DMSO-d₆, ppm): δ 9.97 (s, 1H), 8.82 (d, 1H), 8.57 (s, 1H), 8.50 (t, 2H),7.58 (d, 1H), 4.50 (t, 2H), 4.27-4.32 (m, 1H), 3.90-3.93 (m, 1H), 3.56(t, 4H), 3.34 (s, 2H), 2.31-2.39 (m, 4H), 2.26 (s, 3H).

Example 106 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-2-(morpholinomethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde

Proceeding analogously as described in Example 58, Steps 1-3, butsubstituting2-bromo-3-methyl-5-[2-methyl-4-[6-(trifluoromethyl)-quinazolin-2-yl]phenyl]-3H,3aH,4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-onewith2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one gave the title compound as a white solid.

Step 2: Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-2-(morpholinomethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as in Example 61, but substituting3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehydewith3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehydegave crude product. Purification by Prep-TLC (CH₂Cl₂/MeOH 40:1) gave thetitle compound as a white solid. LC-MS: [M+H]⁺ 537; ¹H-NMR: (300 MHz,DMSO-d₆, ppm): δ 8.80 (d, 1H), 8.69 (d, 1H), 8.62 (d, 1H), 8.26 (d, 1H),8.24-8.27 (m, 2H), 7.55 (s, 1H), 4.47-4.51 (m, 2H), 4.28-4.32 (m, 1H),3.88-3.92 (m, 1H), 3.31-3.57 (m, 6H), 2.08-2.52 (m, 10H).

Example 107 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-2-(4-methylpiperazine-1-carbonyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 62, Step 1, butsubstituting morpholine1-provided crude product. Purification byPrep-TLC (CH₂Cl₂/MeOH 30:1) gave the title compound as a white solid.LC-MS: (ES, m/z): [M+H]⁺ 564.4; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 9.91(s, 1H), 8.74 (s, 1H), 8.56 (s, 1H), 8.49 (d, 1H), 8.26 (t, 2H), 7.56(d, 1H), 4.56-4.59 (m, 2H), 4.31-4.38 (m, 1H), 3.93-3.98 (m, 1H),3.62-3.65 (m, 4H), 2.45-2.50 (m, 7H), 2.36 (s, 3H), 2.23 (s, 3H).

Example 108 Synthesis of2-((4,4-difluoropiperidin-1-yl)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoro-methyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substitutingmorpholine with 4,4-difluoropiperidine provided crude product.Purification by Prep-TLC (CH₂Cl₂/MeOH 40:1) gave the title compound as awhite solid. LC-MS: (ES, m/z): [M−H]⁺571.4; ¹H-NMR: (300 MHz, DMSO-d₆,ppm): δ 9.91 (s, 1H), 8.73 (s, 1H), 8.55 (s, 1H), 8.48 (d, 1H), 8.28 (t,1H), 7.55 (d, 1H), 4.49 (t, 2H), 4.30-4.34 (m, 1H), 4.25-4.28 (m, 1H),3.88-3.94 (m, 1H), 3.55 (s, 1H), 3.31-3.33 (s, 4H), 2.35 (s, 3H), 2.27(s, 3H), 1.90-1.99 (m, 4H).

Example 109 Synthesis of2-((2-hydroxy-2-azaspiro[3.3]heptan-2-yl)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)pyrido[3,2-d]pyrimidin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substitutingmorpholine with 2-azaspiro[3.3]heptan-6-ol (182.35 mg, 1.611 mmol, 5equiv) gave crude product. Purification by Prep-HPLC with the followingconditions (Column: XBridge Prep OBD C18 Column, 30×150 mm 5 um; MobilePhase A: water (0.05% NH₃—H₂O), Mobile Phase B: ACN; Flow rate:60mL/min; Gradient:41% B to 56% B in 7 min; 254; 220 nm; RT: 6.25 min)gave the title compound as a white solid. LC-MS: (ES, m/z): [M+H]⁺563.4; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 9.91 (s, 1H), 8.74 (s, 1H),8.55 (s, 1H), 8.49 (d, 1H), 8.30 (t, 2H), 7.55 (d, 1H), 4.94 (d, 1H),4.47 (t, 2H), 4.26-4.31 (m, 1H), 3.88-3.94 (m, 2H), 3.46 (s, 2H), 3.11(s, 2H), 3.07 (s, 2H), 2.28-2.32 (m, 5H), 2.22 (s, 3H), 1.87 (t, 2H).

Example 110 Synthesis of2-((2-oxa-6-azaspiro[3.5]nonan-6-yl)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoro-methyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substitutingmorpholine with 2-oxa-6-azaspiro[3.5]nonane oxalic acid gave crudeproduct. Purification by Prep-HPLC (Conditions: (2 #SHIMADZU (HPLC-01)):Column, XBridge Prep OBD C18 Column, 19*250 mm, 5 um; mobile phase, and(60% PhaseB up to 70% in 8 min); Detector, UV) gave the title compoundas a white solid. LC-MS: (ES, m/z): [M+H]⁺ 577.3; ¹H-NMR: (300 MHz,DMSO-d₆, ppm): δ 1.40 (s, 2H), 1.61 (s, 2H), 2.25-2.35 (m, 8H), 2.49 (s,2H), 3.47 (s, 2H), 3.88-3.92 (m, 1H), 4.16-4.34 (m, 5H), 4.48 (s, 2H),7.55 (d, 1H), 8.27 (s, 2H), 8.48 (d, 1H), 8.55 (s, 1H), 8.72 (s, 1H),9.89 (s, 1H).

Example 111 Synthesis of2-((2-oxa-6-azaspiro[3.4]octan-6-yl)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 61, but substitutingmorpholine with 2-oxa-6-azaspiro[3.4]octane gave crude product.Purification by Prep-TLC (CH₂Cl₂/MeOH 40:1) gave the title compound as awhite solid. LC-MS: (ES, m/z): [M+H]⁺ 563.4; 1H-NMR: (300 MHz, DMSO-d₆,ppm): δ 9.91 (s, 1H), 8.73 (s, 1H), 8.56 (s, 1H), 8.50 (d, 1H), 8.28 (t,2H), 7.57 (d, 1H), 4.47-4.65 (m, 6H), 4.29-4.36 (m, 1H), 4.05 (s, 1H),3.92-3.97 (m, 2H), 3.44-3.47 (s, 2H), 3.16-3.18 (s, 1H), 2.35-2.51 (m,8H), 1.55 (s, 1H).

Example 112 Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-2-(1-morpholinoethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Step 1: Synthesis of2-(1-hydroxyethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into an 8-mL vial purged under N₂ atmosphere, were placed3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carbaldehyde(100.00 mg, 0.215 mmol, 1.00 equiv), and THF (1.00 mL, 12.343 mmol,57.45 equiv). CH₃MgBr (128.10 mg, 1.074 mmol, equiv) was added at 0° C.and the resulting solution was stirred for 3 h at 0° C. After quenchingthe reaction mixture with water, the product was extracted withdichloromethane and the organic layer was concentrated. The residue wasapplied onto a Prep TLC and eluted with ethyl acetate/petroleum ether(1:1) to give in the title compound (60 mg, 58.00%) as a white solid.

Step 2: Synthesis of2-(1-chloroethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 8-mL vial purged under N₂ atmosphere, were placed2-(1-hydroxyethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (60.00 mg, 0.125 mmol, 1.00 equiv), DCM (1.00 mL, 15.730 mmol,126.23 equiv), and Et₃N (25.22 mg, 0.249 mmol, 2.00 equiv). MsCl (21.41mg, 0.187 mmol, 1.50 equiv) was added at 0° C. and the resultingsolution was stirred for 2 h at 0° C. The reaction was then quenchedwith water and extracted with dichloromethane. The organics were removedin vacuum and the residue was applied onto a Prep TLC and eluted withethyl acetate/petroleum ether (1:2) to give the title compound (50 mg,80.26%) as a white solid.

Step 3: Synthesis of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-2-(1-morpholinoethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 8-mL vial, were placed2-(1-chloroethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (50.00 mg, 0.100 mmol, 1.00 equiv), morpholine (13.07 mg, 0.150mmol, 1.50 equiv), acetone (1.00 mL, 13.602 mmol, 136.00 equiv), K₂CO₃(41.47 mg, 0.300 mmol, 3.00 equiv), and KI (33.21 mg, 0.200 mmol, 2.00equiv). The resulting solution was stirred at 25° C. The reactionmixture was quenched with water and extracted with dichloromethane. Theresidue was applied onto a Prep TLC and eluted with ethylacetate/petroleum ether (1:1) to give the title compound (6.9 mg,12.53%) as a white solid. LC-MS: (ES, m/z): [M+H]⁺ 551.4; ¹H-NMR: (400MHz, CDCl₃, ppm): δ 1.25 (s, 3H), 1.41-1.52 (m, 2H), 2.45-2.80 (m, 8H),3.67-3.98 (m, 6H), 4.23-4.31 (m, 1H), 4.51-4.54 (m, 2H), 7.39 (dd, 1H),8.09 (d, 1H), 8.22 (d, 1H), 8.24 (s, 2H), 8.57 (d, 1H), 8.63 (s, 1H),9.68 (s, 1H).

Example 113 Synthesis of2-amino-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Into a 50-mL round-bottom flask under nitrogen atmosphere, were placed2-bromo-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (200.00 mg, 0.387 mmol, 1.00 equiv), diphenylmethanimine(210.61 mg, 1.162 mmol, 3.00 equiv), toluene (5.00 mL, 46.995 mmol,121.32 equiv), t-BuONa (74.45 mg, 0.775 mmol, 2.00 equiv), Xphos (73.86mg, 0.155 mmol, 0.40 equiv), and Pd(dba)₃CHCl₃ (80.18 mg, 0.077 mmol,0.20 equiv). The resulting solution was stirred overnight at 100° C.Then THF (2 mL) and HOAc (2 mL) were added and the resulting solutionwas stirred for overnight at 25° C. After quenching with water, theresulting solution was extracted with ethyl acetate and the organiclayers combined and concentrated. The residue was applied onto a PrepTLC and eluted with dichloromethane/methanol (30:1) to give the titlecompound (90 mg, 51.35%) 0 as a white solid. LC-MS: (ES, m/z): [M+H]⁺453.3; ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 2.08 (s, 3H), 2.33 (s, 3H),3.82-3.88 (m, 1H), 4.25 (s, 3H), 4.82 (s, 2H), 7.53 (d, 1H), 8.29 (t,2H), 8.48 (d, 1H), 8.55 (s, 1H), 8.73 (s, 1H), 9.91 (s, 1H).

Example 114 Synthesis of7-(hydroxymethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

Proceeding analogously as described in Example 1, Step 9, butsubstituting4-(2-(benzyloxy)ethoxy)-N-(4-bromo-2-methylphenyl)-1-methyl-1H-pyrazole-5-carboxamidewith7-((benzyloxy)methyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one gave crude product. Purification by Prep TLC withdichloromethane/methanol (50:1) gave the title compound as a whitesolid. LCMS: (ES, m/z): [M+H]⁺ 468.3; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ2.26 (s, 3H), 2.35 (s, 3H), 3.77-3.79 (m, 1H), 3.89-3.93 (m, 1H), 4.15(s, 1H), 4.37-4.62 (m, 2H), 5.19-5.31 (m, 1H), 7.51-7.59 (m, 2H), 8.27(t, 2H), 8.49 (d, 1H), 8.55 (s, 1H), 8.73 (s, 1H), 9.87-9.91 (s, 1H).

Example 115 Synthesis of5-(4-(4-hydroxy-6-(trifluoromethyl)quinazolin-2-yl)-2-methylphenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

To a stirred mixture of3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (100.00 mg, 0.230 mmol, 1.00 equiv) in HCl (1M) (5.00 mL) wasadded KMnO₄ (90.00 mg, 0.570 mmol, 2.50 equiv) in portions undernitrogen atmosphere. The resulting mixture was stirred for overnight at100° C. under nitrogen atmosphere. The mixture was allowed to cool toroom temperature and then neutralized to pH 7 with saturated NaHCO₃(aq.). The resulting mixture was extracted with EtOAc and concentratedunder reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc5:1) to afford the title compound (10 mg) as a white solid. LC-MS: ES,m/z): [M+H]⁺ 454.3; ¹H-NMR: (300 MHz, DMSO-d₆, ppm): δ 2.26 (s, 3H),2.31 (s, 3H), 3.87-3.92 (m, 1H), 4.28-4.30 (m, 1H), 4.50-4.54 (m, 2H),7.49 (s, 1H), 7.55 (d, 1H), 7.96-7.98 (m, 2H), 8.08-8.20 (m, 3H), 8.41(s, 1H).

Biological Example

HEPG2 and HEPA1C1C7 cells were maintained in MEM and αMEM withoutnucleosides supplemented with 10% heat inactivated FBS respectively.Stably integrated DRE-luciferase cell lines were generated bytransducing the both cell lines with Cignal XRE luciferase reporter(Qiagen) lentiviral particles according to the manufacturer protocol.For both cell lines stably integrated reporter cell lines were selectedfor the presence of 2 μg/mL puromycin. Following selection of stablyintegrated cell line pools, clonal cell lines were isolated by limitingdilution in 96-well plates. Transcriptional assays were performed byseeding 100 μL of cells at a density of 250,000 or 100,000 cells/mL, forHEPG2 and HEPA1C1C7 DRE-Luc cells respectively, into 96-well cellculture plates in OptiMEM supplemented with 0.5% heat inactivated FBSand allowed to attach overnight. For modulator assays, the compoundswere added in a semi-log dose response using a D300e Digital Dispenser(Tecan) followed normalization with vehicle (DMSO). Immediatelyfollowing compound addition 10 μL of 2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD) was added to the cells to a final concentration of 3 nM or 0.3 nMfor the HEPG2 and HEPA1C1C7 DRE-Luc cells respectively. Following24-hour incubation, the medium was removed and the cells were lysed in25 μL of Reporter Lysis Buffer (Promega). Firefly luciferase activitywas measured immediately following the addition of 50 μL LuciferaseAssay Reagent (Promega). The percent maximal activity for each point wasdetermined using the following equation:(RLU_(sample)−RLU_(vehicle−TCDD))/(RLU_(vehicle+TCDD)RLU_(vehicle−TCDD))*100. The relative IC₅₀, defined as the compoundconcentration required to reduce the TCDD induced response between thetop and bottom plateau of each individual dose response curve by half,for each compound was determined using Prism 7 (GraphPad Software).

TABLE 1 IC₅₀ hAhR Example No. (antagonist mode) 001 ++++ 002 ++++ 003+++ 004 ++++ 005 ++++ 006 ++++ 007 ++++ 008 ++++ 009 ++++ 010 + 011 ++++012 ++ 013 ++++ 014 ++++ 015 ++++ 016 ++++ 017 ++++ 018 +++ 019 ++++ 020++++ 021 ++++ 022 ++++ 023 + 024 ++++ 025 ++++ 026 ++++ 027 ++++ 028++++ 029 ++++ 030 ++++ 031 ++++ 032 + 033 ++++ 034 +++ 035 ++++ 036 ++++037 ++++ 038 ++++ 039 040 + 041 042 +++ 043 + 044 ++++ 045 ++++ 046 ++++047 ++++ 048 ++++ 049 ++++ 050 ++++ 051 +++ 052 ++ 053 +++ 054 +++ 055+++ 056 ++++ 057 ++++ 058 ++++ 059 ++++ 060 +++ 061 ++++ 062 ++++ 063++++ 064 ++++ 065 ++ 066 ++++ 067 ++++ 068 ++++ 069 070 ++++ 071 ++072 + 073 + 074 + 075 + 076 + 077 + 078 + 079 ++++ 080 ++++ 081 ++++ 082++++ 083 ++++ 084 ++++ 085 ++++ 086 ++++ 087 ++++ 088 ++++ 089 ++++ 090++++ 091 ++++ 092 ++++ 093 ++++ 094 ++++ 095 ++++ 096 ++++ 097 ++++ 098++++ 099 ++++ 100 ++++ 101 ++++ 102 ++++ 103 ++++ 104 ++++ 105 ++++ 106++++ 107 ++++ 108 ++++ 109 ++++ 110 ++++ 111 ++++ 112 ++++ 113 ++++ 114++++ ^(i) (+) IC₅₀ = 10 μM-1 μM; (++) IC₅₀ = 1 μM-500 nM; (+++) IC₅₀ =500 nM-200 nM; (++++) IC₅₀ < 200 nM

1. A compound of formula (I′):

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein: each of ring vertices X¹ and X² is C(R^(1a)): or X¹ isC(R^(1a)) and X² is N; Z is selected from the group consisting of:

wherein: the dashed bonds are single or double bonds; n is 0 or 1; W is—C(O)— or —SO₂—; each of ring vertices a, b, c, d, e, f, and g areindependently selected from the group consisting of O, S, N, C(R⁴) andN(R⁴), and the bonds joining the ring vertices are independently singleor double bonds; each R^(1a), R^(1b), R^(1c), R^(1d) and R^(1e) isindependently selected from the group consisting of hydrogen, deuterium,halogen, —CN, —NO₂, —R^(c), —CO₂R^(a), —CONR^(a)R^(b), —C(O)R^(a),—OC(O)NR^(a)R^(b), —NR^(b)C(O)R^(a), —NR^(b)C(O)₂R^(c),—NR^(a)C(O)NR^(a)R^(b), —NR^(a)R^(b), —OR^(a), and —S(O)₂NR^(a)R^(b);wherein each R^(a) and R^(b) is independently selected from hydrogen,C₁₋₈ alkyl, C₃₋₆ cycloalkyl and C₁₋₈ haloalkyl, or when attached to thesame nitrogen atom can be combined with the nitrogen atom to form afour-, five- or six-membered ring having from 0 to 2 additionalheteroatoms as ring members selected from N, O, S, SO or SO₂; each R^(c)is independently selected from the group consisting of C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ deuteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₃₋₆cycloalkyl, and wherein the aliphatic and cyclic portions of R^(a),R^(b) and R^(c) can be further substituted with from one to threehalogen, hydroxy, Cia alkyl, C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, diC₁₋₄ alkylamino and carboxylic acid groups; each R^(2a), R^(2b), R^(2c)and R^(2d) is independently selected from the group consisting ofhydrogen, halogen, C₁₋₃ alkyl, C₁₋₃ deuteroalkyl, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃ deuteroalkoxy and C₁₋₃ haloalkoxy; R³ is selected from thegroup consisting of hydrogen, deuterium, C₁₋₃ alkyl, C₁₋₃ deuteroalkyl,C₁₋₃ alkylene-OR^(d), C₁₋₃ alkylene-CO₂R^(d), C₁₋₃ alkylene-NR^(d)R^(e),C₁₋₃ alkylene-CONR^(d)R^(e), C₁₋₃ alkylene-OC(O)NR^(d)R^(e), and C₁₋₃alkylene-NR^(e)C(O)₂R^(f); or two R³ groups are combined to form oxo(═O); each R⁴ is independently selected from the group consisting ofhydrogen, halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),—OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d), —NR^(e)C(O)₂R^(f),—NR^(d)C(O)NR^(d)R^(e), —NR^(d)R^(e), —OR^(d), —S(O)₂NR^(d)R^(e),—X^(a)—CN, —X^(a)—CO₂R^(d), —X^(a)—CONR^(d)R^(e), —X^(a)—C(O)R^(d),—X^(a)—OC(O)NR^(d)R^(e), —X^(a)—NR^(e)C(O)R^(d),—X^(a)—NR^(e)C(O)₂R^(f), —X^(a)—NR^(d)C(O)NR^(d)R^(e),—X^(a)—NR^(d)R^(e), —X^(a)—OR^(d), —X^(a)—S(O)₂NR^(d)R^(e), and—X^(a)—OP(O)(OH)₂; wherein each X^(a) is independently C₁₋₆alkylene; andeach R^(d) and R^(e) is independently selected from hydrogen, C₁₋₈alkyl, and C₁₋₈ haloalkyl, or when attached to the same nitrogen atomcan be combined with the nitrogen atom to form either (i) a four-, five-or six-membered ring having from 0 to 3 additional heteroatoms as ringmembers selected from N, O, C(O), S, SO or SO₂ or (ii) aspiroheterocycloalkyl ring; each R^(f) is independently selected fromthe group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ deuteroalkyl,C₃₋₆ cycloalkyl, C₃₋₆ heterocycloalkyl, phenyl and 5- or 6-memberedheteroaryl; and wherein the aliphatic and cyclic portions of R^(d),R^(e) and R^(f) can be further substituted with from one to threehalogen, hydroxy, benzyloxy, C₁₋₄ alkyl, C₁₋₄ alkoxy, amino, C₁₋₄alkylamino, di C₁₋₄ alkylamino, tetrazolyl, and carboxylic acid groups.2. The compound of claim 1 wherein: the dashed bonds are single bonds;vertex a is selected from the group consisting of O, S, N, CH(R⁴) andN(R⁴); each of ring vertices b, c, d, e, f, and g are independentlyselected from the group consisting of O, S, N, C(R⁴) and N(R⁴), and thebonds joining the ring vertices are independently single or doublebonds.
 3. The compound of claim 2 wherein Z has subformula A′. 4.(canceled)
 5. The compound of claim 2 wherein Z has subformula C′. 6.(canceled)
 7. (canceled)
 8. The compound of claim 3, wherein Z isselected from the group consisting of:


9. (canceled)
 10. (canceled)
 11. The compound of claim 5, wherein Z isselected from the group consisting of:


12. The compound of claim 11 wherein W is —C(O)—.
 13. The compound ofclaim 11 wherein W is —SO₂—.
 14. The compound of claim 8 wherein W is—C(O)—.
 15. The compound of claim 8 wherein W is —SO₂—.
 16. (canceled)17. (canceled)
 18. (canceled)
 19. The compound of claim 8 wherein R^(1b)is selected from the group consisting of H, deuterium, halogen, C₁₋₄alkyl, —OC₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OC₁₋₄ haloalkyl. 20.(canceled)
 21. The compound of claim 19 wherein R^(1c), R^(1d) andR^(1c) are each independently selected from the group consisting of H,deuterium, halogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl and OC₁₋₄ haloalkyl. 22.The compound of claim 21 wherein R^(2a), R^(2b), R^(2c), R^(2d) areindependently selected from the group consisting of H, deuterium,halogen, C₁₋₄ alkyl and C₁₋₄ haloalkyl.
 23. (canceled)
 24. (canceled)25. (canceled)
 26. (canceled)
 27. The compound of claim 22 wherein eachR⁴ is independently selected from the group consisting of H, halogen,CN, —R^(e), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d), —NR^(e)C(O)R^(d),—NR^(e)C(O)₂R^(f)—NR^(d)C(O)NR^(d)R^(e), —NR^(d)R^(e), —OR^(d),—X^(a)—CN, —X^(a)—CO₂R^(d), —X^(a)—CONR^(d)R^(e), —X^(a)—C(O)R^(d),—X^(a)—OC(O)NR^(d)R^(e), —X^(a)—NR^(e)C(O)R^(d),—X^(a)—NR^(e)C(O)₂R^(f), —X^(a)—NR^(d)C (O)NR^(d)R^(e),—X^(a)—NR^(d)R^(e) and —X^(a)—OR^(d); wherein each X^(a) isindependently C₁₋₄ alkylene. In further selected embodiments, each eachR⁴ is independently selected from the group consisting of hydrogen,halogen, —CN, —R^(f), —CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),—NR^(d)R^(e), —OR^(d), —X^(a)—CN, —X^(a)—CO₂R^(d), X^(a)—NR^(d)R^(e),and —X^(a)—OR^(d) wherein each X^(a) is independently C₁₋₆alkylene. 28.(canceled)
 29. The compound of claim 1 having a structure of formula(I):

wherein: Z is selected from the group consisting of:

each R⁴ is independently selected from the group consisting of hydrogen,halogen, —CN, —R^(f)—CO₂R^(d), —CONR^(d)R^(e), —C(O)R^(d),—OC(O)NR^(d)R^(e), —NR^(e)C(O)R^(d),—NR^(e)C(O)₂R^(f)—NR^(d)C(O)NR^(d)R^(e), —NR^(d)R^(e), —OR^(d),—S(O)₂NR^(d)R^(e), —X^(a)—CN, —X^(a)—CO₂R^(d), —X^(a)—CONR^(d)R^(e),—X^(a)—C(O)R^(d), —X^(a)—OC(O)NR^(d)R^(e), —X^(a)—NR^(e)C(O)R^(d),—X^(a)—NR^(e)C(O)₂R^(f)—X^(a)—NR^(d)C(O)NR^(d)R^(e), —X^(a)—NR^(d)R^(e),—X^(a)—OR^(d), and —X^(a)—S(O)₂NR^(d)R^(e); wherein each X^(a) isindependently C₁₋₆alkylene; and each R^(d) and R^(e) is independentlyselected from hydrogen, C₁₋₈ alkyl, and C₁₋₆ haloalkyl, or when attachedto the same nitrogen atom can be combined with the nitrogen atom to forma four-, five- or six-membered ring having from 0 to 2 additionalheteroatoms as ring members selected from N, O, S, SO or SO₂; andwherein the aliphatic and cyclic portions of R^(d), R^(e) and R^(f) arecan be further substituted with from one to three halogen, hydroxy, C₁₋₄alkyl, C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, di C₁₋₄ alkylamino andcarboxylic acid groups.
 30. (canceled)
 31. The compound of claim 29,having formula (IIa), (IIc), (IId), (IIe) (IIf), (IIIa), (IIIb), (IIId),(IVa), (IVc) or (IVd):


32. (canceled)
 33. (canceled)
 34. The compound of claim 1 selected from:7-(2,5-dimethyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one;3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one;5-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one;3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)quinolin-2-yl)phenyl)-6,7-dihydropyrazolo-[1,5-a]pyrazin-4(5H)-one;6-(2,5-dimethyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;6-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;7-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one;3-methyl-5-(2-methyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one;5-(2,5-dimethyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one;5-(2,5-dimethyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one;5-(2-fluoro-5-methyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one;5-(2,5-dimethyl-4-(6-(trifluoromethyl)quinolin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one;5-(2-fluoro-5-methyl-4-(6-(trifluoromethyl)quinolin-2-yl)phenyl)-3-methyl-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one;1-methyl-6-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;1-methyl-6-(2-methyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one;1-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one;1-methyl-7-(2-methyl-4-(8-methyl-6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one;7-(2,5-dimethyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one;7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-3H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one;2-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)-phenyl)-6,7-dihydro-2H-[1,2,3]triazolo[4,5-f][1,4]oxazepin-8(5H)-one;6-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one;2-methyl-7-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one;7-(4-(6-fluoro-1,5-naphthyridin-2-yl)-2-methylphenyl)-1-methyl-6,7-dihydro-1H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one;2-(hydroxymethyl)-3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-quinazolin-2-yl)phenyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one;3-methyl-5-(2-methyl-4-(6-(trifluoromethyl)-1,5-naphthyridin-2-yl)phenyl)-2-(morpholinomethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one; or a pharmaceutically acceptable salt thereof.
 35. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.
 36. A method of treating cancerin a subject in need thereof, said method comprising administering tosaid subject an effective amount of a compound of claim
 1. 37.(canceled)
 38. (canceled)